JP2023522621A - Immunomodulatory treatment improves immune response and reduces immune paralysis - Google Patents

Abstract

Kind Code: A1 The present invention relates to methods of treating immunoparalysis by attenuation through removal of inflammatory mediator and/or checkpoint inhibitor proteins in a subject, comprising pore sizes ranging from about 50 Å to about 3000 Å and a pore volume of dry polymer of about 0.5 cc/g to about 3.0 cc/g, or a pore size ranging from about 50 Å to about 40000 Å and a dry polymer of about 0.5 cc/g to about 5.0 cc/g Treating a subject with a therapeutically effective amount of a porous biocompatible polymeric adsorbent comprising a polymeric pore volume. [Selection diagram] Fig. 1

Description

This application is related to US Patent Application No. 63/009,515, filed April 14, 2020, the entire disclosure of which is incorporated herein.

One or more of the inventions disclosed herein were made with Government support under Contract No. N66001-12-C-4199 awarded by the Defense Advanced Research Projects Agency and SSC Pacific. The government may have certain rights in this invention.

The present invention relates to immunomodulatory therapies for the treatment of conditions or serious injuries affected by excessive levels of inflammatory or anti-inflammatory mediators and/or immune checkpoint proteins leading to an immunosuppressive state called immunoparalysis. is. Anergy is synonymous with immune paralysis.

Many diseases, acute and chronic diseases, syndromes and severe injuries cause abnormal immune responses leading to multiple organ failure, infections, failure to heal and increased mortality. Immunoparalysis is thought to play an important role in such progression.

Sepsis is an example of a high mortality syndrome for which there is no clinical solution. In the United States alone, approximately 1.7 million patients develop sepsis each year, and approximately 270,000 die from multiple organ failure (https://www.cdc.gov/features/get-ahead). -sepsis/index.html). Sepsis is caused by bacteria, viruses and fungi. The most common cause of sepsis is bacteria and the most common symptom is pneumonia (https://www.nigms.nih.gov/education/Documents/Sepsis.pdf). Although this syndrome has been studied for decades, treatment options are still limited to supportive care. This includes antibiotics, vasodilators, mechanical ventilation (for acute respiratory syndrome secondary to sepsis), fluid therapy. Unfortunately, these options do not treat the underlying inflammatory response dysregulation, nor the immunodeficiency that occurs during or after sepsis. Immunodeficiency, which begins early in the inflammatory phase and can persist after the systemic inflammatory release syndrome (SIRS) phase subsides, is now recognized as the leading cause of death in patients with sepsis and septic shock (van Ton , Annemieke M. Peters, et al."Precision immunotherapy for sepsis."Frontiers in immunology 9 (2018)). Loss of immune system function can significantly impair healing and recovery, increase the risk of infection, cause abnormal tissue remodeling, and many other complications.

The adverse effects of sepsis on the immune system are significant and are known to affect both innate and adaptive immune responses. Leukocyte trafficking and function are impaired, making the body highly susceptible to nosocomial infections and low-pathogenic pathogens. In sepsis, activated leukocytes adhere to activated endothelial tissue and produce proteolytic enzymes and reactive oxygen species for removal of pathogens. As sepsis progresses, this response becomes uncontrolled and impairs the chemotaxis of activated leukocytes throughout the body regardless of the site of infection, leading to tissue damage and subsequent multi-organ failure. After sepsis, patients are more likely to require additional intensive care unit (ICU) visits and have a higher 5-year mortality compared with other populations [Pavon, Arnaud, et al. "Profile of the risk of death after septic shock in the present era: an epidemiological study." Critical care medicine 41.11 (2013): 2600-2609; Jensen, Isaa cJ. , et al. "Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity." The Journal of Immunology 200.5 (2018): 1543-1553].

An example of the multifactorial effects of sepsis on the body is an inflammatory cytokine storm, resulting in massive production of pro- and anti-inflammatory mediators. Suspected sepsis is routinely treated with supportive care, including fluid therapy, antibiotics, and vasodilators; I can't hold back. As a result, if left untreated, this cytokine storm, also known as systemic inflammatory release syndrome (SIRS), can lead to organ failure, increased susceptibility to nosocomial infections and low-pathogenic pathogens, and possibly death. It propagates the aftereffects of inflammation. Cytokine storms and excessive inflammatory responses can also directly cause apoptosis of immune effector cells, further weakening the immune response and contributing to immunosuppression.

Attenuates excessive inflammatory responses by removing circulating inflammatory cytokines, interleukins (ILs), chemokines, tumor necrosis factors, interferons, lymphokines upregulated to pathological levels Adsorption technology therapy will limit the progression and severity of the body's overcompensated anti-inflammatory response and immune paralysis [Chousterman, Benjamin G.; , Filip K. Swirski, and GeorgF. Weber. "Cytokine storm and sepsis disease pathogenesis." Seminars in immunopathology. Vol. 39. No. 5. Springer Berlin Heidelberg, 2017. ].

When a patient recovers from initial sepsis, the immune system does not return to homeostasis. The immune system remains immunosuppressed, ie, immunoparalyzed, for months to years, making it highly vulnerable to low-pathogenic pathogens and infectious diseases. Immunocompromised patients often have an excess of anti-inflammatory mediators and cytokines (IL-1 receptor antagonists, IL-4, IL-10, IL-11, IL-13, etc.) that impair immune system activation, function, May interfere with or reduce reactivity. Immune checkpoint proteins such as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1 (programmed cell death protein 1), and T cell immunoglobulin mucin 3 (TIM-3) have also been reported. B-and T-lymphocyte attenuator (BTLA), natural killer cell receptor, NKG2D (natural killer group 2, member D), lymphocyte activation gene 3 (LAG-3), and their respective ligands are upregulated. ing. This can lead to immune cell dysfunction, including exhaustion of T cells, suppression of neutrophil and monocyte function, and promotion of apoptosis. Adsorbents that directly remove these inhibitory cytokines, receptors, and their ligands, as well as their soluble forms, may allow the body to restore immune system function, thereby restoring or limiting immunodeficiency. not [Patera, Andriani C.; , et al. "Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD -1or PD-L1."Journal of Leukocyte Biology. 100.6 (2016): 1239-1254]

Another example leading to immunodeficiency is acute and chronic liver failure. Studies have shown that the progression of this condition includes an abnormal immune response and multiple organ failure. Some cells, such as dendritic cells and lymphocytes, have increased apoptosis, while others, such as neutrophils, have decreased apoptosis. Changes in these cells cause the immune system to weaken or fail completely, leading to immunoparalysis and weakened immune system [Chousterman, Benjamin G.; , Filip K. Swirski, and GeorgF. Weber. "Cytokine storm and sepsis disease pathogenesis." Seminars in immunopathology. Vol. 39. No. 5. Springer Berlin Heidelberg, 2017. ].

Age-related immunosenescence increases the risk of immunodeficiency. Impaired immune responses and T-cell function are similar in immunosenescence and immunodeficiency, both of which have been shown to result in increased systemic inflammatory responses and upregulation of immune checkpoint proteins such as PD-1. [Sokoya, T.; , et al. "HIV as a Cause of Immune Activation and Immunosence."Mediators of information (2017)].

A biomarker for immunoparalysis is human leukocyte antigen-DR (HLA-DR). In sepsis and septic shock, monocyte HLA-DR expression is decreased [Volka, Hans-Dieter, Petra Reinkeb, and Wolf-Dierich Dockea. "Clinical Aspects: From Systemic Inflammation to 'Immunoparalysis'." do.

In some embodiments, the present invention provides a therapeutically effective amount of a porous biological material comprising a pore size ranging from about 50 Å to about 3000 Å and a pore volume between about 0.5 cc/g and about 3.0 cc/g dry polymer. It relates to a method of treating immunoparalysis in a subject comprising treating the subject with a compatible polymeric adsorbent. Adsorbents can be administered extracorporeally, or can be administered intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, or intranasally.

In some embodiments, the present invention provides a therapeutically effective amount of a The present invention relates to a method of treating immunoparalysis in a subject comprising treating the subject with a porous biocompatible polymeric adsorbent. Adsorbents can be administered extracorporeally, or can be administered intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, or intranasally.

Some adsorbents are made with at least one crosslinker and at least one monomer.

Preferred monomers include divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate, Ethyl acrylate, vinyl toluene, vinyl naphthalene, vinyl benzyl alcohol, vinyl formamide, methyl methacrylate, methyl acrylate, tribyl benzene, divinyl naphthalene, tribyl cyclohexane, divinyl sulfone, trimethylolpropane trimethacrylate, tripropane remethacrylate, trimethylolpropane Dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate , dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide.

In some embodiments, the crosslinker is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane Acrylates, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol including one or more of tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, divinylformamide.

Certain adsorbents are additionally prepared using one or both of at least one dispersant and at least one porogen.

Some adsorbents include a biocompatible, blood compatible outer coating covalently bonded to the adsorbent by free radical graft polymerization.

In some embodiments, the sorbent is administered prior to administration of supportive care. In other embodiments, the sorbent is administered concurrently with the administration of supportive care. In still other embodiments, the sorbent is administered after administration of supportive care. Supportive care may include antibiotics, fluid resuscitation, and vasoactive drugs.

Administration of sorbents can ameliorate various symptoms experienced by a subject. In some embodiments, administration of the sorbent reduces the severity of immune paralysis. In other embodiments, administration of the sorbent increases HLA-DR function. In still other embodiments, administration of the sorbent reduces the damage to the body caused by the hyperinflammatory response, thereby reducing the patient's risk of immune paralysis. Administration of adsorbents can also reduce T cell exhaustion.

In some embodiments, administration of the sorbent results in the removal of one or more of a) inflammatory or anti-inflammatory mediators, and b) proteins and their corresponding ligands, including soluble forms, from the subject's bodily fluids. . In certain embodiments, administration of the adsorbent is effective for lymphocytes (e.g., T cells, B cells, natural killer cells), neutrophils (granulocytes), monocytes, macrophages, dendritic cells, eosinophils, and Resulting in partial or total restoration of immune cell function, such as basophils. Proteins include CTLA-4, PD-1, TIM-3, BTLA, natural killer cell receptor, NKG2D, LAG-3, and PD-L1, PD-L2, MICA, ULBP2, FasL, CTLA-4, MHC It may also include one or more of each ligand, such as class II, CD40L. Inflammatory or anti-inflammatory mediators may include one or more of the interleukins, cytokines, chemokines, interferons, lymphokines, tumor growth factors, complement factors, or members of the tumor necrosis factor family. In certain embodiments, adsorbents are used to remove PD-L1.

Various suitable adsorbents are disclosed herein. In some embodiments, the sorbent comprises residues of one or more of divinylbenzene and ethylvinylbenzene, styrene, and ethylstyrene monomers.

Some embodiments of the present invention provide therapeutically effective amounts of porous biomaterials comprising pore sizes ranging from about 50 Å to about 3000 Å and pore volumes between about 0.5 cc/g and about 3.0 cc/g dry polymer. The present invention relates to a method of reducing sepsis and inflammation-related T-cell dysfunction or other immune cell dysfunction in a subject comprising treating the subject with a polymeric sorbent. The adsorbent can be administered extracorporeally, or it can be administered intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, or intranasally.

Some embodiments of the present invention provide a therapeutically effective amount of porosity comprising a pore size ranging from about 50 Å to about 40,000 Å and a pore volume between about 0.5 cc/g and about 5.0 cc/g dry polymer. A method of reducing sepsis and inflammation-associated T-cell dysfunction or other immune cell dysfunction in a subject comprising treating the subject with a biocompatible polymeric adsorbent. The adsorbent can be administered externally, intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, or intranasally.

FIG. 1 is data from a benchtop evaluation showing the mean percent clearance of sPD-L1 using CytoSorb and controls from bovine whole blood. Data are means±SEM. D. and each group was evaluated in triplicate (n=3). CytoSorb 60 and 120 indicate the amount of CytoSorb used (60 mL and 120 mL respectively). Controls 60 and 120 are control groups (Sham, no CytoSorb) evaluated at the same time as the treatment (CytoSorb) group. FIG. 2 is a plot of cytokine adsorption (time versus % survival) from CytoSorb versus control whole blood. FIG. 2A is directed to the adsorption of IFN-γ. FIG. 2B is directed to adsorption of IL-6. FIG. 2C is directed to adsorption of MIP-1α. FIG. 2D is directed to adsorption of TNF-α. Percent survival is taken from the mean±SEM of four runs. ^* p<0.05. FIG. 3 shows a plot of adsorption of DAMPS from whole blood (time vs. % survival) for CytoSorb versus control. FIG. 3A is directed to adsorption of C5a. FIG. 3B is directed to adsorption of HMGB-1. FIG. 3C is directed to adsorption of procalcitonin. FIG. 3D is directed to adsorption of S100-A8. Percentage remaining is taken from the mean±SEM of four runs. ^* p<0.05. Figure 4 is a plot of adsorption of bacterial PAMPS from whole blood (spiked with serum spiked with S. pyrogenic exotonin B, Staph TSST-1 or Staph aureus α-toxin) for CytoSorb versus control (time versus % survival). ). FIG. 4A is directed to α-toxin adsorption. FIG. 4B is directed to adsorption of SpeB. FIG. 4C is directed to adsorption of TSST-1. Percentage remaining is taken from the mean±SEM of four runs. ^* p<0.05.

The present invention relates to immunomodulatory therapies for the treatment of conditions or serious injuries affected by compromised immune system function, immunosuppression, allergies, or immunoparalysis. A weakened immune system results in reduced healing and recovery, poor response to infectious stimuli and increased risk of infection and sepsis, poor immune response to vaccination, increased risk of malignancies, abnormal tissue remodeling, and other complications. can result in This includes infections, sepsis and septic shock, trauma, burns, liver disease, pancreatitis, surgical complications, arteriosclerosis, allograft vascular disease, encephalomyelitis, stroke, sepsis and viral myocarditis, cardiac ischemia. Short- and long-term poor prognosis seen in critical illness including, but not limited to, diseases such as reperfusion injury (IR), myocardial infarction, acute and chronic liver failure, as well as treatment of age-related conditions such as immunosenescence. may contribute [Davies, Roger, Kieran O'Dea, and Anthony Gordon. "Immune therapy in sepsis: Are we ready to try again?." Journal of the Intensive Care Society 19.4 (2018): 326-344; Baban, Babak, et al. "Upregulation of programmed death-1 and its ligand in cardiovascular injury models: interaction with GADD153." adjust The application of sorbent technology for immunization during and/or after these critical conditions as a way to minimize the severity or effects of immunosuppression during and/or after these critical conditions. As a way of minimizing the severity of the paralysis, as a way of allowing the immune response to return to homeostasis during and after these severe conditions.

As required, detailed embodiments of the present invention are disclosed herein. It should be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be construed as limitations, but merely as a basis for teaching one skilled in the art to employ the invention. is. The following specific examples will enable a better understanding of the invention. However, they are given for guidance only and do not imply any limitation.

The present invention may be more readily understood by reference to the following detailed description taken in conjunction with the accompanying figures and examples that form a part of this disclosure. The invention is not limited to the particular materials, devices, methods, applications, conditions or parameters described and/or illustrated herein, and the terminology used herein exemplifies particular embodiments. It is to be understood that it is for illustrative purposes only and is not intended to limit the claimed invention. As used herein, the term "plurality" means more than one. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it is to be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

It is to be understood that certain features of the invention that are, for clarity, described in this specification in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that, for brevity, are described in the context of a single embodiment may also be provided separately or in any subcombination. Further, reference to values stated in ranges include each value and combination of values within that range.

The immune system is tightly regulated by pro- and anti-inflammatory mediators, cells, and other factors to prevent hyperinflammatory and immunosuppressive effects. However, in critically ill patients, immune system homeostasis is often compromised, which can result in excessive inflammatory responses and severe immunosuppression, allergies, and immunoparalysis. Excessive inflammatory responses, for example, induce apoptosis of immune effector cells and upregulation of endothelial cell adhesion molecules that aberrantly sequester infection-fighting leukocytes to the vascular endothelium of healthy organs and away from sites of infection, leading to compensatory effects. It can also paradoxically cause immunosuppression later in the disease, such as causing a rebound anti-inflammatory response, also called anti-inflammatory response syndrome (CARS). CARS is often characterized by severe immunosuppression due to, for example, loss of immune effector cells and upregulation of immunosuppressive or regulatory cells (eg, T regulatory cells) and overexpression of anti-inflammatory mediators. For example, one class of anti-inflammatory mediators includes anti-inflammatory cytokines (eg, interleukins, interferons, etc.). Another class is immune checkpoint proteins. Immune checkpoints regulate the immune system's response to infections, malignancies, and prevent autoimmunity. For example, the immune checkpoint protein PD-1 is expressed on activated T cells and plays a central role in the downregulation of these cells. Activation of PD-1 by the membrane-bound ligands PD-L1 and PD-L2 and the soluble ligands sPD-L1 and sPD-L2 leads to T cell apoptosis and immunosuppression. The PD-1/PD-L1 pathway is one of the most extensively studied pathways and increased expression of these proteins has been associated with immunosuppression. PD-1 is expressed on many cells such as T cells, B cells, and NK cells. Expression of PD-L1 has been confirmed in monocytes, neutrophils, etc. Many checkpoint inhibitor proteins are upregulated in patients with sepsis-induced immunosuppression, which alters immune cell function.

Excessive inflammatory responses, also called cytokine storms, are episodes of highly elevated inflammatory and anti-inflammatory systemic immune responses due to a variety of circumstances, including trauma, disease, autoimmune syndromes, and medical interventions.

Definitions The following definitions are intended to aid in understanding the invention.

Some of the quantitative expressions given herein are not qualified with the term "about." All quantities given herein are meant to refer to the actual given value, and whether or not the term "about" is explicitly used, and It is understood to mean an approximation of the given value that would reasonably be inferred based on the ordinary skill of one of ordinary skill in the art, including approximation by experimental and/or measurement conditions.

Throughout the description and claims of this specification, for example, "comprise" and "contain" and variants of these words "comprising" and "comprises" means "including but not limited to" and is not intended (and does not exclude) to exclude other ingredients. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. .

The term "subject" means any animal, particularly a mammal, most particularly a human, treated or to be treated by a method according to an embodiment of the present invention. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, non-human primates (NHPs) such as cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys or apes, humans, and the like. not, but more particularly humans.

“Immune deficiency” refers to a stage in which immune homeostasis is not restored leading to immunosuppression. It is also called anergy.

The term "biocompatible" is defined to mean that the adsorbent is capable of contact with physiological fluids, living tissue, or organisms during contact without causing unacceptable clinical changes.

As used herein, the terms "treat", "treating" or "treatment" of any disease, condition, syndrome or disorder refer, in one embodiment, to ameliorating the disease, condition, syndrome or disorder. (ie, delaying or halting or reducing the onset of at least one of the disease or its clinical symptoms). In another embodiment, "treat," "treat," or "treatment" refers to alleviating or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In further embodiments, "treat," "treating," or "treatment" refers to treating a disease, condition, syndrome, or disorder by treating a disease, condition, syndrome, or disorder physically (e.g., with identifiable symptoms). stabilization), physiological (eg, stabilization of a physical parameter), or both. In yet another embodiment, "treat," "treat," or "treatment" refers to preventing or delaying the onset or development or progression of a disease, condition, syndrome, or disorder.

"Hemocompatibility" is defined as a state in which a biocompatible material produces a clinically acceptable physiological change when contacted with whole blood or plasma.

As used herein, the term "physiological fluid" refers to fluids originating in the body, including nasopharynx, oral cavity, esophagus, stomach, pancreas, liver, pleura, pericardium, peritoneum, intestine, prostate, seminal fluid, Vaginal secretions Vaginal secretions, as well as tears, saliva, pulmonary or bronchial secretions, mucus, bile, blood, lymph, plasma, serum, synovial fluid, cerebrospinal fluid, urine, and interstitial fluid, intracellular fluid, extracellular fluid It may include, but is not limited to, fluids such as those exuding from burns and wounds.

As used herein, the term "adsorbent" includes adsorbents and absorbents.

For the purposes of the present invention, the term "sorb" is defined as "uptake and binding by absorption and/or adsorption".

"Supportive care" means conventional treatments used to address symptoms of immunodeficiency. Examples of supportive care include antibiotics, vasodilators, mechanical ventilation and extracorporeal membrane oxygenation (for acute respiratory syndrome secondary to sepsis), hemodialysis and hemofiltration (due to renal impairment), and fluid therapy. be done.

For purposes of the present invention, the term "perfusion" means passing a physiological fluid, once through or by a suitable extracorporeal circuit, through a device containing a porous polymeric adsorbent to remove toxic molecules from the fluid. is defined as removing

Hemoperfusion is a special case of perfusion in which the physiological fluid is blood.

A "dispersant" is defined as a substance that finely divides and stabilizes immiscible liquid droplets suspended in a fluid medium.

The term "heparin-mimetic polymer" refers to any polymer that has the same anticoagulant and/or antithrombotic properties as heparin. In some embodiments, the adsorbent can act as a heparin mimetic polymer by having functional groups selected from —SO ₃ H.

-COOH and -OH (or salts thereof) are present on the adsorbent surface. These functional groups can be attached to the adsorbent polymer by means known to those skilled in the art. For example, Ran, et al. Macromol. Biosci. 2012, 12(1), 116-25. Suitable salts include sodium and potassium salts such as -SO ₃ ^{-M +} , -COO ^- M ⁺ , -O ^- M ⁺ , where M is Na or K.

The term “macroreticular synthesis” is used to force growing polymer molecules out of the monomer liquid at a certain molecular size defined by phase equilibrium, yielding solid nanosized microgel particles with spherical or near-spherical symmetry. given, defined as the polymerization of monomers to polymers in the presence of an inert precipitant packed together with beads having physical pores of open-cell structure [U.S. Pat. No. 4,297,220, Meitzner and Oline, October 27, 1981; L. Albright, Reactive Polymers, 4, 155-174 (1986)].

The term "hypercrosslinked" refers to polymers in which a single repeat unit has 2 or more connectivity. Hypercrosslinked polymers are prepared by crosslinking swollen or dissolved polymer chains with a large number of rigid bridging spacers rather than copolymerization of monomers. Cross-linking agents include bis(chloromethyl) derivatives of aromatic hydrocarbons, methylal, monochlorodimethyl ether, and other bifunctional compounds that react with polymers in the presence of Friedel-Crafts catalysts [Tsyurupa, M.; P. , Z. K. Blinnikova, N.; A. Proskurina, A.; V. Pastukhov, L.; A. Pavlova, and V.A. A. Davankov. "Hypercrosslinked Polystyrene: The First Nanoporous Polymeric Material." Nanotechnologies in Russia 4 (2009): 665-75. ]

Pathogen-associated molecular pattern molecules (PAMPS) are molecules derived from microorganisms that are recognized by cells of the innate immune system. These molecules have small molecular motifs that are conserved within the class of microorganisms and are recognized. initiates and perpetuates pathogen-induced inflammatory responses via Toll-like receptors and pattern recognition receptors.

Damage-associated molecular pattern molecules (DAMPS) are host biomolecules that are released from stressed cells and initiate and sustain inflammation in response to trauma, ischemia, and tissue injury, with or without pathogenic infection. It's about.

Adsorbents One embodiment of the present invention is a porous polymeric adsorbent. Porous polymeric adsorbents are designed to adsorb cytokines, interleukins, chemokines, tumor necrosis factors, interferons, lymphokines, soluble checkpoint inhibitor ligands, and other proteins involved in immune paralysis from physiological fluids from patients. configured to In certain embodiments, the sorbent is configured to remove such proteins from the patient's blood.

Some preferred polymers are acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, cetyl acrylate, cetyl methacrylate, 3,4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate. , dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, vinyl benzene, vinyl formamide, vinyl naphthalene, vinyl sulfone, 3,4-epoxy-1-butene , 1,2-epoxy-9-decene, 1,2-epoxy-5-hexene, ethyl acrylate, ethyl methacrylate, ethylstyrene, ethylvinylbenzene, glycidyl methacrylate, methyl acrylate, methyl methacrylate, acrylic acid Octyl, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, Trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinyl-1-cyclohexene 1,2-epoxy, vinylformamide, vinylonaphthalene, 2-vinyl There are also examples of polymers containing residues from one or more monomers selected from oxiranes, vinyltoluenes, and the like, or monomers containing same, or mixtures thereof, and including polymers containing such monomers.

In some embodiments of the present invention, organic solvents and/or polymeric porogens can be used as porogens or pore-forming agents to obtain porous polymers through consequent phase separation induced during polymerization. Some preferred porogens are benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanone, decane, dibutyl phthalate, di-2-ethylhexyl phthalate, di-2-ethylhexyl phosphate, ethyl acetate, 2-ethyl-1-hexanoate, 2 -ethyl-1-hexanol, n-heptane, n-hexane, isoamyl acetate, isoamyl alcohol, n-octane, pentanol, poly(propylene glycol), polystyrene, poly(styrene co-methyl methacrylate), tetralin, toluene, tri-n -butyl phosphate, 1,2,3-trichloropropane, 2,2,4-trimethylpentene, xylene, and the like, or a mixture comprising any combination thereof.

In yet another embodiment, the dispersant is hydroxyethylcellulose, hydroxypropylcellulose, poly(diethylaminoethyl acrylate), poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl acrylate) poly(dimethylaminoethyl methacrylate), poly(hydroxy ethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), salts of poly(methacrylic acid), and mixtures thereof selected from the group comprising

Preferred adsorbents are biocompatible. In another further embodiment, the polymer is biocompatible. In yet another embodiment, the polymer is hemocompatible. In yet another embodiment, the biocompatible polymer is hemocompatible. In yet another embodiment, the shape of the polymer is spherical beads.

In another embodiment, the biocompatible polymer comprises poly(N-vinylpyrrolidone).

In another embodiment, the biocompatible polymer consists of 1,2-diols. In another embodiment, the biocompatible polymer comprises a 1,3-diol.

In another further embodiment, the biocompatible polymer comprises a heparin mimetic polymer.

A coating/dispersion on poly(styrene-co-divinylbenzene) resin can improve biocompatibility.

In yet another embodiment, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinyl Naphthalene, divinyl sulfone, pentaerythritol diacrylate, pentaerythritol diethacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, trimethylolpropane diacrylate, trimethylolpropane A group of crosslinkers consisting of dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, and mixtures thereof can be used to form blood compatible hydrogel coatings. .

In some embodiments, the polymer is a polymer comprising at least one crosslinker and at least one dispersant. Dispersants may be biocompatible. Dispersants include hydroxyethyl cellulose, hydroxypropyl cellulose, poly(diethylaminoethyl acrylate), poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl acrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly( hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), poly(hydroxypropyl methacrylate), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) from these chemicals, compounds or materials and mixtures thereof selected from the group consisting of dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipenta Erythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol tri Methacrylates, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane and mixtures thereof. Preferably, the polymer is developed at the same time as the coating is formed and the dispersant is chemically bound or entangled with the surface of the polymer.

In yet another embodiment, the biocompatible polymer coating is poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), It is selected from the group consisting of poly(hydroxypropyl methacrylate), poly(N-vinylpyrrolidone), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof.

In yet another embodiment, the biocompatible oligomer coating is poly(diethylaminoethyl methacrylate), poly(dimethylaminoethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl acrylate), It is selected from the group consisting of poly(hydroxypropyl methacrylate), poly(N-vinylpyrrolidone), poly(vinyl alcohol), salts of poly(acrylic acid), salts of poly(methacrylic acid) and mixtures thereof.

Some current biocompatible adsorbent compositions are composed of multiple pores. This biocompatible adsorbent is designed to adsorb a wide range of toxins from less than 0.5 kDa to 1,000 kDa. Without wishing to be bound by theory, it is believed that the adsorbents work by trapping molecules of a given molecular weight within the pores. The size of molecules that can be sorbed by a polymer increases as the pore size of the polymer increases. Conversely, if the pore size is increased beyond the optimal pore size for adsorption of a given molecule, adsorption of that protein can or will be reduced.

In certain embodiments, the structure of some polymers is such that the total pore volume for pore sizes ranging from 50 Å to 3000 Å is between 0.5 cc/g and 3.0 cc/g dry polymer. be.

In some embodiments, the polymer has a pore structure such that the total pore volume for pore sizes ranging from 50 Å to 3000 Å is greater than 0.5 cc/g to 3.0 cc/g. 0 cc/g of dry polymer, wherein the ratio of the pore volume between 50 Å and 3000 Å (pore diameter) of the polymer to the pore volume between 500 Å and 3000 Å (pore diameter) is less than 200:1, and 50 Å and 3000 Å of the polymer (pore diameter) and pore volume ratio between 1,000Lu_1FA and 3000Lu_1FA (pore diameter) is greater than 20:1.

In certain embodiments, the solid form is porous. Some solid forms are characterized by having a pore structure with a total volume of pore sizes greater than 0.1 cc/g and less than 5.0 cc/g of dry polymer in the range of 10 Å to 40,000 Å. be.

In certain embodiments, the adsorbent comprises a pore structure such that the total pore volume for pore sizes ranging from 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry polymer, wherein and the ratio of 50 Å to 40,000 Å (pore diameter) to 1000 Å to 10000 Å (pore diameter) of the adsorbent is less than 2:1.

Immediate Disclosure adsorbents that may be suitable for use in immunotherapy are biocompatible polymeric adsorbents that have the following characteristics.

pore sizes ranging from about 50 Å to about 3000 Å, alternatively from about 60 Å to about 2000 Å, alternatively from about 75 Å to about 3000 Å, alternatively from about 50 Å to about 2000 Å, alternatively from about 100 Å to about 1500 Å, and about 0. It has a pore volume between 5 cc/g and about 3.0 cc/g dry polymer.

In certain embodiments, the structure of some polymers is such that the total pore volume for pore sizes ranging from 50 Å to 3000 Å is 0.5 cc/g to 3.0 cc/g dry polymer. . In some embodiments, the polymer has a pore structure such that the total pore volume for pore sizes ranging from 50 Å to 3000 Å is greater than 0.5 cc/g to 33.0 cc/g, wherein The ratio of the pore volume between 50 Å to 3000 Å (pore diameter) and the pore volume between 500 Å to 3000 Å (pore diameter) of the polymer is less than 200:1, and the polymer has a pore volume between 50 Å to 1000 Å (pore diameter) and 1000 Lu_1 FA to 3000 Lu_1 FA (pore diameter) The pore volume ratio between is greater than 20:1.

In certain embodiments, the adsorbent comprises a pore structure such that the total pore volume for pore sizes ranging from 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry adsorbent; Here the ratio of the 50 Å to 40,000 Å (pore diameter) pore volume of the adsorbent to the 1000 Å to 10000 Å (pore diameter) is less than 2:1.

In certain embodiments, the adsorbent is a dry polymer with a pore structure having a total volume of pore sizes in the range of 10 Å to 10,000 Å and 0.5 cc/g to 3.0 cc/g; the ratio of the pore volume between 10 Å and 3,000 Å to the pore volume between 500 Å and 3,000 Å of the crosslinked polymer material is less than 7:1; The ratio of pore volume between 10 Å and 3000 Å diameter to pore volume between diameters is less than 2:1.

In some embodiments, the sorbent has:
a) a pore structure in which at least ⅓ of the pore volume of pores with diameters between 50 Å and 40,000 Å is in pores with diameters between 100 Å and 1,000 Å, or (b) 50 Å and a pore structure in which at least one-half of the pore volume in pores with diameters between 40,000 Å are pores with diameters between 1000 Å and 10,000 Å; or (c) diameters between 50 Å and 40,000 Å at least 1/3 of the pore volume in the pores having a diameter of between 10,000 Å and 40,000 Å.

In some other methods, the solid form is non-porous.

In certain embodiments, the polymer can be in the form of beads with diameters ranging from 0.1 micrometers to 2 centimeters. Certain polymers are in the form of powders, beads, or other regularly or irregularly shaped particulates.

In some embodiments, the plurality of solid forms comprises particles having diameters within the range of 0.1 micrometers to 2 centimeters.

In some embodiments, the sorbent comprises a crosslinked polymer resulting from the reaction of a crosslinker with one or more of the following polymerizable monomers, followed by epoxidation and ring opening to form a polyol: acrylonitrile , allyl glycidyl ether, butyl acrylate, butyl methacrylate, cetyl acrylate, cetyl methacrylate, 3,4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, di Pentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3,4-epoxy-1-butene, 1,2-epoxy-9-decene, 1 , 2-epoxy-5-hexene, ethyl acrylate, ethyl methacrylate, ethyl styrene, ethyl benzene, glycidyl methacrylate, methyl acrylate, methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, penta Erythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, It may include trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinylcyclohexene 1,2-epoxy, vinylformamide, vinylonaphthalene, 2-vinyloxirane and vinyltoluene. In preferred adsorbents, the polyol formed is a diol.

In another embodiment, polymeric adsorbents are prepared from the reaction of a cross-linking agent with vinyl acetate and then modified to form beads containing polyol groups. This reaction may be a copolymerization or a one-pot reaction in which vinyl acetate is added after the first polymerization is nearly complete, utilizing unused initiator to initiate a second free-radical polymerization. to add vinyl acetate groups to the surface of the polymer beads. Subsequent modification of vinyl acetate-containing polymers is the sequence of hydrolysis to convert the acetate groups to hydroxyl groups, reaction with epichlorohydrin to form polymer beads containing epoxide groups, and ring opening to convert the epoxide groups to polyol groups. is done in In preferred embodiments, the polyol is a diol.

Some embodiments of the present invention directly synthesize polymeric beads containing epoxide groups and then ring-open the epoxide groups to form polyols. One or more of the following polymerizable vinyl monomers containing epoxide groups can be polymerized in the presence of crosslinkers and monomers to give polymeric beads containing the above functional groups: allyl glycidyl ether, 3,4- Dihydroxy-1-butene, 3,4-epoxy-1-butene, 1,2-epoxy-9-decene, 1,2-epoxy-5-hexene, glycidyl methacrylate, 4-vinyl-1-cyclohexene 1,2 -epoxides, and 2-vinyloxiranes. Epoxide group-containing vinyl monomers can also be copolymerized with hemocompatible monomers (such as NVP.2-HEMA) to obtain epoxide group-containing hemocompatible beads. In preferred embodiments, the polyol is a diol.

Yet other embodiments include hypercrosslinked polymeric sorbents containing polyol groups on the bead surface. This can be achieved by free radicals or S _N 2 type chemical reactions. Chemical modification of the adsorbent bead surface is facilitated by the remarkable peculiarity of hypercrosslinked polystyrene in the case of the modifications described above; namely, the reactive functional groups of the polymer are primarily located on its surface. Hypercrosslinked polystyrene is generally prepared by crosslinking polystyrene chains with large amounts of difunctional compounds, particularly compounds with two reactive chloromethyl groups. The latter is a two-step reaction in which two phenyl groups of adjacent polystyrene chains are alkylated by a Friedel-Crafts reaction to generate two molecules of HCl to form a crosslink. During the cross-linking reaction, the formed three-dimensional network acquires rigidity. This property gradually slows down the second step of the cross-linking reaction, because the reduced mobility of the second pendant functional group of the first cross-linking reagent makes it possible to add a suitable second partner to the alkylation reaction. This is because it becomes more and more difficult. This is especially characteristic of secondary functional groups that happen to be exposed on the surface of the beads. Thus, the largest, if not the majority, of the pendant unreacted chloromethyl groups in the final hypercrosslinked polymer are located on the bead surface (or pore surface). In this context, the surface of polymeric beads is predominantly modified by engaging the chloromethyl groups in a variety of chemical reactions that allow the attachment of biocompatible and hemocompatible monomers and/or crosslinkers or low molecular weight oligomers. It becomes possible to Subsequently, hydroxyl groups are introduced and reacted with epichlorohydrin to obtain a polymeric adsorbent containing epoxide groups on the surface of the beads. These epoxide groups can then be ring-opened to form polyol groups. In some preferred embodiments the polyol is a diol.

In other embodiments, hypercrosslinked polystyrene containing pendant unreacted chloromethyl groups is treated with one or more of the following: (±)-3-amino-1,2-propanediol, glycerol, and other polyol reagents. directly below to form adsorbent polymer beads with polyols on the surface of the beads (or the surface of the pores). In preferred embodiments, the polyol is a diol.

In yet another embodiment, the biocompatible and hemocompatible agent of the surface coating, poly(vinyl alcohol), also acts as a polyol functional group.

In some other embodiments, the sorbent comprises a crosslinked polymer resulting from the reaction of a crosslinker with one or more of the following polymerizable monomers, followed by polymerization in the presence of a free radical initiator: Reaction with ionic monomers: acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, cetyl acrylate, cetyl methacrylate, 3,4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate. , dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate. Dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3,4-epoxy-1-butene, 1,2-epoxy-9-decene, 1,2-epoxy-5-hexene, acrylic acid Ethyl, ethyl methacrylate, ethyl styrene, ethyl bilbedin, glycidyl methacrylate, methyl acrylate, methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate , pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl Included are alcohols, 4-vinylcyclohexene 1,2-epoxy, vinylformamide, vinylonaphthalene, 2-vinyloxirane and vinyltoluene. Polymerizable zwitterionic monomers include one or more of the following: 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt, [3-(acryloylamino)propyl]-trimethylammonium chloride, 3-[[2-(acryloyloxy)ethyl]-dimethylammonio]-propionic acid, [2-(acryloyloxy)ethyl]-dimethyl-(3-sulfopropyl)-ammonium hydroxide, 2-acryloyloxy Ethylphosphorylcholine, [3-(methacryloylamino)propyl]-trimethylammonium chloride, 3-[[2-(methacryloyloxy)ethyl]-dimethylammonio]-propionic acid, [2-(methacryloyloxy)ethyl]- dimethyl-(3-sulfopropyl)ammonium hydroxide and 2-methacryloyloxyethylphosphorylcholine.

In certain embodiments, the polymers of the present invention are formulated in an aqueous phase with free radical initiation in the presence of an aqueous phase dispersant selected to provide a biocompatible and hemocompatible outer surface to the formed polymeric beads. manufactured by suspension polymerization at In some embodiments, the beads are synthesized by omentum synthesis using an appropriately selected porogen (pore-forming agent) and an appropriate time-temperature profile of polymerization to develop the appropriate pore structure. made porous.

In another embodiment, polymers made by suspension polymerization can be made biocompatible and hemocompatible by further grafting biocompatible and hemocompatible monomers or low molecular weight oligomers. . It has been shown that the radical polymerization procedure does not consume all the vinyl groups of the DVB introduced into the copolymerization. On average, about 30% of the DVB species do not function as cross-linking bridges, leaving only one of the two vinyl groups involved in the network. Therefore, the presence of large amounts of pendant vinyl groups is characteristic of the adsorbent. It is expected that these pendant vinyl groups will preferably be exposed on the surface of the polymeric bead and should be readily available for chemical modification if its macropores are present. Chemical modification of the surface of DVB-copolymers relies on chemical reaction of the pendant vinyl groups exposed on the surface, with the aim of converting these groups into more hydrophilic functional groups. This transformation by free-radical grafting of monomers, crosslinkers, and small oligomers provides the first hydrophobic adsorbents with blood-compatible properties.

In yet another embodiment, the radical polymerization initiator is first added to the dispersed organic phase rather than the aqueous carrier medium typical of suspension polymerization. During polymerization, many growing polymer chains with their chain-end radicals appear at the phase interface and can initiate polymerization in the dispersion medium. In addition, radical initiators such as benzoyl peroxide generate radicals relatively slowly. This initiator is only partially consumed during bead formation even after several hours of polymerization. This initiator readily migrates toward the surface of the bead and activates the surface-exposed pendant vinyl groups of the divinylbenzene portion of the bead, thus allowing graft polymerization of other monomers added after the reaction has proceeded for a period of time. to start. Thus, free-radical grafting can occur during the transformation of monomer droplets into polymeric beads, thereby incorporating monomers, crosslinkers, and low molecular weight oligomers that confer biocompatibility and blood compatibility as surface coatings.

In some embodiments, impurities are removed using hemoperfusion and perfusion devices. The hemoperfusion and perfusion apparatus is equipped with retainer screens at both the outlet and inlet ends to maintain the bead bed within the vessel, or within the flow-through vessel with a trailing retainer screen to collect the beads after mixing. consisting of a packed bead bed of polymeric beads. Hemodialysis and perfusion are performed by passing blood through a bead bed filled with whole blood, plasma, physiological saline, or the like. During perfusion through the bead bed, toxic molecules are retained by sorption, tortuous pathways, and/or pore trapping, while the remaining fluid and intact cellular constituents pass essentially unchanged in concentration.

In another embodiment, the in-line filter consists of a bead bed of polymeric beads packed into a flow-through container with retainer screens at both the outlet and inlet ends to retain the bead bed within the container. The biological/physiological fluid is passed once by gravity from the storage bag through the filled bead bed, during which toxic molecules are retained by sorption, tortuosity and pore entrapment, while remaining fluid and intact cells The components pass through substantially unchanged in concentration.

In certain other embodiments, the sorbent is administered as a pharmaceutical composition. Pharmaceutical compositions can also be administered in tablets, capsules, gel capsules, slurries, suspensions, and the like. The manufacture of such pharmaceutical compositions is well known in the art.

Penetration enhancers can also be used in the instant pharmaceutical compositions. Such enhancers include surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants and are commonly known in the art.

In some preferred embodiments, administration of the sorbent polymer is orally, or rectally, or via a feeding tube, or any combination thereof.

The polymers of the invention can be administered to a patient once or multiple times.

Polymers useful in the present invention can be supplied as slurries, suspensions, or reconstituted from dry to slurries or suspensions. In some embodiments, the polymer may be supplied as a slurry or suspension packaged in either single-dose or multi-dose bottles for oral administration. In other embodiments, the polymer may be supplied as a slurry or suspension packaged in either single or multi-dose bottles for administration by enema or feeding tube or any combination thereof. In certain embodiments, the polymer is supplied as a dry powder that can be wetted externally or within the gastrointestinal tract with or without the addition of a wetting agent such as ethyl alcohol.

The polymer may be supplied as tablets, capsules or suppositories packaged in bottles or blister packs for administration. Depending on the application, the polymer may be sterile or non-sterile. The polymer may be sterilized by standard methods. Such methods are well known to those skilled in the art.

Specific polymers useful in the present invention (as is or after further modification) are macromolecules prepared from polymerizable monomers of styrene, divinylbenzene, ethylvinylbenzene, and acrylate and methacrylate monomers such as those listed below by manufacturer. Porous Polymers: Rohm and Haas Company, (now part of The Dow Chemical Company), Amberlite™ XAD-1, Amberlite™ XAD-2, Amberlite™ XAD -4, Amberlite™ XAD-7, Amberlite™ XAD-7HP, Amberlite™ XAD-8, Amberlite™ XAD-16, Amberlite™ XAD-16HP, Amberlite™ XAD-16HP (trademark) XAD-18, Amberlite (trademark) XAD-200, Amberlite (trademark) XAD-1180, and other macroporous polymer solid stating agents. Amberlite™ XAD-2000, Amberlite™ XAD-2005, Amberlite™ XAD-2010, Amberlite™ XAD-761, and Amberlite™ XE-305 with Amberchrom™ ) CG 71, s, m, c, Amberchrom™ CG 161, s, m, c, Amberchrom™ CG 300, s, m, c and Amberchrom™ CG 1000, s, m, c chromatography grades something like a solid phase. Dow Chemical Company: Dowex™ Optipore™ L-493, Dowex™ Optipore™ V-493, Dowex™ Optipore™ V-502, Dowex™ Optipore™ L- 285, Dowex™ Optipore™ L-323 and Dowex™ Optipore™ V-503. Lanxess (formerly Bayer, Chibron). Lewatit™ VPOC 1064 MD PH, Lewatit™ VPOC 1163, Lewatit™ OC EP 63, Lewatit™ S 6328A, Lewatit™ OC 1066, and Lewatit™ 60/150 MIBK. Mitsubishi Chemical Corporation: Diaion (trademark) HP 10, Diaion (trademark) HP 20, Diaion (trademark) HP 21, Diaion (trademark) HP 30, Diaion (trademark HP 40, Diaion (trademark) HP 50, Diaion (trademark) SP70, Diaion (trademark) SP 205, Diaion (trademark) SP 206, Diaion (trademark) SP 207, Diaion (trademark) SP 700, D Diaion (trademark) SP 800, Diamond AEON™ SP 825, DIAION™ SP 850, DIAION™ SP 875, DIAION™ HP 1MG, DIAION™ HP 2MG, DIAION™ CHP 55A, DIAION™ ( Trademark) CHP 55Y, Diaion (trademark) CHP 20A, Diaion (trademark) CHP 20Y, Diaion (trademark) CHP 2MGY, Diaion (trademark) CHP 20P, Diaion (trademark) HP 20SS, Diaion (trademark) SP 20SS, Diaion™ SP 207SS Purolite: Purosorb™ AP 250, Purosorb™ AP 400, Kaneka Corp. Lixelle beads.

Other particular polymers useful in the present invention (as is or after further modification) are cellulosic porous materials. Such modifications may include the addition of lipophilic substrates containing aryl or alkyl groups, along with polyol or zwitterionic groups added via free radical or S _N 2 type chemistry.

Methods of Treatment/Use of Adsorbents in Immunomodulatory Therapy Embodiments of the present invention are directed to immunomodulatory therapy for treating conditions or severe conditions affected by upregulation of immune checkpoint proteins leading to immunoparalysis. Examples of such conditions include sepsis and septic shock, trauma, burns, liver disease, pancreatitis, atherosclerosis, allograft vascular disease, encephalomyelitis, stroke, sepsis and viral myocarditis, cardiac ischemia. Treatment of age-related conditions such as, but not limited to, blood reperfusion (IR) injury, myocardial infarction, acute on chronic liver failure, and immunosenescence. Immunomodulatory therapy utilizes the adsorbents of the instant disclosure alone or in combination with supportive therapies such as checkpoint inhibitors, monoclonal antibodies, and/or bispecific T cell engagement. When a sorbent is used in combination with supportive therapy, the supportive therapy can be administered before, simultaneously with, or after the sorbent. It is contemplated that the adsorbent will remove one or more immune checkpoint proteins when used in the intended method. In one embodiment, it is contemplated that the adsorbent removes PD-L1 and/or PD-L2, and/or their soluble counterparts sPD-L1 and/or PD-L2.

When used in immunomodulatory therapy, sorbents may reduce the severity of immunoparesis and/or increase HLA-DR function. Alternatively, the use of sorbents reduces the damage to the body caused by hyperinflammatory reactions, thereby reducing the patient's risk of immunocompromise. In another embodiment, adsorbents can be used to reduce exhaustion of T cells.

In alternative embodiments, the adsorbent may be used to remove one or more of a) cytokines and b) soluble ligands from the subject's bodily/physiological fluids. Exemplary soluble ligands include one or more of PD-L1, PD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. Exemplary cytokines include one or more members of the family of interleukins, chemokines, interferons, lymphokines, tumor growth factors, or tumor necrosis factors. In one embodiment, the soluble ligand is PD-L1 and/or PD-L2.

When used in immunoadsorption therapy, use of the adsorbent can result in a reduction of inflammatory mediators in the subject. In one embodiment, the use of sorbents results in removal of inflammatory mediators. In another embodiment, adsorbents are used to remove anti-inflammatory mediators. In another embodiment, adsorbents are used to remove cytokines. In other embodiments, adsorbents may be used to remove checkpoint inhibitor proteins, or their soluble counterparts.

In other embodiments, when used for immunomodulatory therapy, the adsorbent may provide partial or complete restoration of T cell function.

Various non-limiting scenarios illustrate the process of instant invention:
Scenario 1. Adsorbents are used to treat immunoparalysis by removing factors that inhibit the immune response to pathogens and other stimuli.
Scenario 2. The adsorbent modulates the immune system during or after treatment of the subject with conventional supportive care.
Scenario 3. Adsorbents are used in the treatment of immunosenescence.
Scenario 4. Combined use of adsorbents and supportive care improves overall effectiveness.

Certain embodiments of the present invention are directed to methods of treating immunodeficiencies in subjects in need thereof utilizing the porous biocompatible polymeric adsorbents of the present disclosure. A method of treating immunoparesis may attenuate immunoparesis. In certain embodiments, the method reduces the severity of immunoparesis and/or increases HLA-DR function. The method also reduces the damage to the body caused by the hyperinflammatory response, thereby reducing the patient's risk of immunocompromise.

Methods of treating immunodeficiency remove inflammatory (which can induce apoptosis of immune effector cells and rebound anti-inflammatory responses) and anti-inflammatory mediator and/or checkpoint inhibitor proteins and their soluble counterparts from patients That is. In other embodiments, the adsorbent results in the removal of one or more of a) cytokines and b) soluble ligands from the subject's body/physiologic fluids. In certain embodiments, the soluble ligand is one or more of PD-L1, PD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. In one embodiment, the soluble ligand is PD-L1. In other embodiments, cytokines include one or more members of the interleukin, chemokine, interferon, lymphokine, tumor growth factor, or tumor necrosis factor families. In another embodiment, the adsorbent reduces T cell exhaustion.

In certain embodiments of the method of treating immunoparalysis, the adsorbent is used in combination with other supportive care. The sorbent may be provided/administered before, after, or concurrently with supportive care. Similarly, supportive therapy may be administered before, after, or concurrently with supportive therapy.

In one embodiment, a method of treating immunoparalysis in a subject in need thereof comprises adding a physiological fluid to the subject with pore sizes ranging from about 50 Å to about 3000 Å and from about 0.5 cc/g to about 3.0 cc/g. Contacting with a porous biocompatible polymeric adsorbent containing a pore volume between dry polymers.

In another embodiment, a method of treating immunoparalysis in a subject in need thereof comprises adding the subject's physiological fluid to pore sizes ranging from about 50 Å to about 40,000 Å and having pore sizes ranging from about 0.5 cc/g to about 5 contacting with a porous biocompatible polymeric adsorbent containing a pore volume of 0.0 cc/g dry polymer.

The method removes inflammatory mediators and/or checkpoint proteins. In certain embodiments, the contacting step comprises administering the adsorbent intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, or subcutaneously, or intranasally. In other embodiments, the sorbent is extracorporeal. In preferred embodiments, the physiological fluid is blood.

In embodiments, a method of treating immunoparalysis in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent has a pore size ranging from about 50 Å to about 3000 Å. and a pore volume of between about 0.5 cc/g to about 3.0 cc/g dry polymer, characterized by administering to contact the sorbent with a physiological fluid of interest. In preferred embodiments, the physiological fluid is blood.

In another embodiment, a method of treating immunoparalysis in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent has a thickness of about 50 Å to about 40,000 Å. and a pore volume between about 0.5 cc/g to about 5.0 cc/g dry polymer, the step of administering placing the adsorbent in contact with the physiological fluid of interest. In preferred embodiments, the physiological fluid is blood.

In an alternative embodiment, the method of treating immunoparalysis in a subject in need thereof comprises a pore size ranging from about 50 Å to about 3000 Å and a fineness between about 0.5 cc/g to about 3.0 cc/g dry polymer. Providing the subject with a porous, biocompatible polymeric adsorbent comprising a pore volume. In an alternative embodiment, a method of treating immunoparalysis in a subject in need thereof comprises a range of pore diameters between about 50 Å and about 40,000 Å and about 0.5 cc/g to about 5.0 cc/g. g. Providing the subject with a porous biocompatible polymeric adsorbent comprising a pore volume between the dry polymer.

Another embodiment of the present invention is a pore size ranging from about 50 Å to about 3000 Å and a pore volume between about 0.5 cc/g and about 3.0 cc/g dry polymer for use in treating immunoparalysis. is the use of porous biocompatible polymeric adsorbents comprising:

Another embodiment of the present invention is a pore size ranging from about 50 Å to about 40,000 Å and a pore volume between about 0.5 cc/g and about 5.0 cc/g dry polymer for use in treating immunoparalysis. is the use of porous biocompatible polymeric adsorbents comprising:

An alternative embodiment of the present invention is a pore size range from about 50 Å to about 3000 Å and pores between about 0.5 cc/g and about 3.0 cc/g dry polymer in the manufacture of a medicament for treating immunoparalysis. The use of porous biocompatible polymeric adsorbents containing volume.

An alternative embodiment of the present invention is a pore size range of about 50 Å to about 40,000 Å and a The use of porous biocompatible polymeric adsorbents containing pore volume.

Any of the features described for methods of treating immunoparalysis are applicable to such applications.

Certain embodiments of the present invention are directed to methods of treating immunosenescence in a subject in need thereof utilizing the porous biocompatible polymeric adsorbents of the present disclosure. Similar to methods of treating immunosenescence, methods of treating immunosenescence can result in removal of one or more of a) cytokines and b) soluble ligands from the subject's body/physiologic fluids. In certain embodiments, the soluble ligand is one or more of PD-L1, PD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. In one embodiment, the soluble ligand is PD-L1. In other embodiments, cytokines include one or more members of the interleukin, chemokine, interferon, lymphokine, tumor growth factor, or tumor necrosis factor families.

In certain embodiments of the method of treating immunosenescence, the adsorbent is used in combination with other supportive care. The sorbent may be provided/administered before, after, or concurrently with supportive care. Similarly, supportive therapy may be administered before, after, or concurrently with supportive therapy.

In one embodiment, a method of treating immunosenescence in a subject in need thereof comprises adding the subject's physiological fluid to pore sizes ranging from about 50 Å to about 3000 Å and from about 0.5 cc/g to about 3.0 cc/g with a porous biocompatible polymeric adsorbent containing a pore volume between the dry polymer of .

In another embodiment, a method of treating immunosenescence in a subject in need thereof comprises applying the subject's physiological fluid to a pore size ranging from about 50 Å to about 40,000 Å and having a pore size ranging from about 0.5 cc/g to about 5.5 cc/g. Contacting with a porous biocompatible polymeric adsorbent comprising a dry interpolymer pore volume of 0 cc/g.

The method removes inflammatory mediators and/or checkpoint proteins. In certain embodiments, the contacting step comprises administering the adsorbent intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, or subcutaneously, or intranasally. In other embodiments, the sorbent is extracorporeal. In preferred embodiments, the physiological fluid is blood.

In another embodiment, a method of treating immunosenescence in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent ranges from about 50 Å to about 3000 Å. and a pore volume between about 0.5 cc/g and about 3.0 cc/g dry polymer, and administering to contact the sorbent with a physiological fluid of interest. In preferred embodiments, the physiological fluid is blood.

In another embodiment, a method of treating immunosenescence in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent has a thickness of about 50 Å to about 40,000 Å. and a pore volume between about 0.5 cc/g to about 5.0 cc/g dry polymer, and the administering comprises contacting the adsorbent with a physiological fluid of interest. In preferred embodiments, the physiological fluid is blood.

In an alternative embodiment, the method of treating immunosenescence in a subject in need thereof comprises a pore size ranging from about 50 Å to about 3000 Å and a pore volume between about 0.5 cc/g and about 3.0 cc/g dry polymer. providing a subject with a porous biocompatible polymeric adsorbent comprising:

In an alternative embodiment, a method of treating immunosenescence in a subject in need thereof comprises a pore size ranging between about 50 Å to about 40,000 Å and a dry polymer providing the subject with a porous biocompatible polymeric adsorbent comprising an interstitial pore volume.

Another embodiment of the present invention provides pore sizes ranging from about 50 Å to about 3000 Å and pore volumes between about 0.5 cc/g and about 3.0 cc/g dry polymer for use in treating immunosenescence. is the use of porous biocompatible polymeric adsorbents comprising:

Another embodiment of the present invention is a pore size range of about 50 Å to about 40,000 Å and fine particles between about 0.5 cc/g to about 5.0 cc/g dry polymer for use in treating immunosenescence. The use of porous biocompatible polymeric adsorbents containing pore volume.

An alternative embodiment of the present invention is a pore size range from about 50 Å to about 3000 Å and pores between about 0.5 cc/g and about 3.0 cc/g dry polymer in the manufacture of a medicament for treating immunosenescence. The use of porous biocompatible polymeric adsorbents containing volume.

An alternative embodiment of the present invention is a pore size range from about 50 Å to about 40,000 Å and pores between about 0.5 cc/g and about 5.0 cc/g dry polymer in the manufacture of a medicament for treating immunosenescence. The use of porous biocompatible polymeric adsorbents containing volume.

Any of the features described for methods of treating immunosenescence are applicable to such uses.

Certain embodiments of the present invention are directed to methods of treating sepsis and/or inflammation-related T cell dysfunction in a subject in need thereof utilizing the porous biocompatible polymeric adsorbents of the present disclosure. there is In one embodiment, the method treats sepsis. In another embodiment, the method treats inflammation-associated T-cell dysfunction. In an alternative embodiment, the method treats both sepsis and inflammation-related T cell dysfunction. In another embodiment, the method treats anti-inflammatory or immunosuppressive-related T cell dysfunction. In an alternative embodiment, the method treats both sepsis and anti-inflammatory or immunosuppressive-related T cell dysfunction.

In one embodiment of the invention, a method of treating sepsis and/or inflammation-related T cell dysfunction in a subject in need thereof comprises adding a physiological fluid to the subject with pore sizes ranging from about 50 Å to about 3000 Å and about 0 contacting with a porous biocompatible polymeric adsorbent comprising a pore volume between 0.5 cc/g and about 3.0 cc/g dry polymer.

In another embodiment of the invention, a method of treating sepsis and/or inflammation-related T-cell dysfunction in a subject in need thereof comprises adding a physiological fluid to the subject with pore sizes ranging from about 50 Å to about 40,000 Å. and a porous biocompatible polymeric adsorbent comprising a pore volume between about 0.5 cc/g and about 5.0 cc/g dry polymer.

The method may remove inflammatory mediators, and/or checkpoint proteins. The method may also comprise administering the adsorbent intravenously, intramuscularly, intratumorally, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. Alternatively, the sorbent is extracorporeal. In preferred embodiments, the physiological fluid is blood.

In embodiments, a method of treating sepsis and/or inflammation-associated T-cell dysfunction in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent comprises about The administration comprises contacting the sorbent with a physiological fluid of interest, comprising a pore size in the range of 50 Å to about 3000 Å and a pore volume between about 0.5 cc/g to about 3.0 cc/g dry polymer. In preferred embodiments, the physiological fluid is blood.

In another embodiment, a method of treating sepsis and/or inflammation-related T-cell dysfunction in a subject in need thereof comprises administering to the subject a porous biocompatible polymeric adsorbent, wherein the polymeric adsorbent is , a pore size in the range of about 50 Å to about 40,000 Å and a pore volume between about 0.5 cc/g and about 5,0 cc/g dry polymer, and administering to contact the sorbent with a physiological fluid of interest. include. In preferred embodiments, the physiological fluid is blood.

In yet another embodiment, a method of treating sepsis and/or inflammation-related T-cell dysfunction in a subject in need thereof comprises a pore size ranging from about 50 Å to about 3000 Å and a pore size ranging from about 0.5 cc/g to about 3.5 cc/g. Providing a subject with a porous biocompatible polymeric adsorbent comprising a pore volume of 0 cc/g dry polymer.

In yet another embodiment, a method of treating sepsis and/or inflammation-related T cell dysfunction in a subject in need thereof comprises a pore size ranging from about 50 Å to about 40,000 Å and a providing to the subject a porous biocompatible polymeric sorbent comprising a pore volume between about 5.0 cc/g dry polymer.

In certain embodiments of the methods of treating sepsis and/or inflammation-related T-cell dysfunction, the adsorbent is used in combination with other supportive care. The sorbent may be provided/administered before, after, or concurrently with supportive care. Similarly, supportive therapy may be administered before, after, or concurrently with supportive therapy.

Another embodiment of the present invention provides pore sizes ranging from about 50 Å to about 3000 Å and about 0.5 cc/g to about 3.0 cc/g for use in treating sepsis and/or inflammation-related T cell dysfunction. The use of porous biocompatible polymeric adsorbents containing pore volume between dry polymers.

Another embodiment of the present invention provides a pore size range of about 50 Å to about 40,000 Å and about 0.5 cc/g to about 5.0 cc for use in treating sepsis and/or inflammation-related T cell dysfunction. The use of porous biocompatible polymeric adsorbents containing pore volumes between 1/g dry polymer.

An alternative embodiment of the present invention is a pore size range of about 50 Å to about 3000 Å and about 0.5 cc/g to about 3.0 cc /g dry polymer.

An alternative embodiment of the present invention is the manufacture of a medicament for treating T cell dysfunction associated with sepsis and/or inflammation with pore sizes ranging from about 50 Å to about 40,000 Å and Use of porous biocompatible polymeric adsorbents containing about 5.0 cc/g dry interpolymer pore volume.

Any of the features described for methods of treating T cell dysfunction associated with sepsis and/or inflammation are applicable to such uses.

In certain embodiments of the method or use, the adsorbent adsorbs PD-L1, PD-L2, or their soluble counterparts.

In certain embodiments of the method or use, the adsorbent sorbs anti-inflammatory cytokines.

As used herein, when a method refers to administering, administering includes accessing the sorbent to a physiological fluid. For example, if the fluid is blood, access may be achieved by placing a sorbent within or connected to the blood vessel.

The following examples are intended to be illustrative and non-limiting. The following examples of the invention are intended to further illustrate the nature of the invention. It is believed that one of ordinary skill in the art, using the preceding description and the following illustrative examples, can make and use the invention, and perform the claimed method. It should be understood that the following examples do not limit the invention, the scope of the invention being determined by the appended claims.

Example 1: Synthesis of Base Solvents CY14175 & CY15077
Reactor setup: A 4-neck glass lid was attached to a 3 L jacketed cylindrical glass reaction vessel using stainless steel flange clamps and PFTE gaskets. The lid was fitted with a PFTE stirrer bearing, RTD adapter, and water-cooled reflux condenser. A stainless steel stirrer shaft with five 60° agitators was threaded through the stirrer bearing and inserted into a digital overhead stirrer.RTD was connected to a PolyStat circulation heating and cooling unit via a corresponding adapter. Matching tubing was used to connect the inlet and outlet of the reaction vessel jacket to the appropriate ports on the PolyStat. An unused port on the lid was used to charge the reactor and was otherwise left plugged in.

Polymerization: The compositions of the aqueous and organic phases are shown in Tables I and II below, respectively. I put it in. Poly(vinyl alcohol) (PVA), which has a degree of hydrolysis of 85.0-89.0 mol% and a viscosity of 23.0-27.0 cP in a 4% aqueous solution at 20° C., is dispersed in the water of the first flask and heated. Heated to 80° C. with stirring on a plate. Salts (see Table 1, MSP, DSP, TSP, sodium nitrite) were dispersed in water in a second flask and heated to 80° C. with stirring on a hot plate. Circulation of the heat transfer medium from the polystat into the reactor jacket was started to heat the fluid temperature to 60°C. Once the PVA and salt dissolved, both solutions were charged into the reactor one at a time using a glass funnel. The digital overhead stirrer was turned on and the rpm was set to a value that produced the appropriate droplet size during the organic phase addition. The temperature of the water phase in the kettle was set at 70°C. The organic phase was prepared by adding benzoyl peroxide (BPO) to divinylbenzene (DVB) in a 2 L Erlenmeyer flask and shaking until completely dissolved. 2,2,4-Trimethylpentane and toluene were added to the flask and shaken to mix well. When the temperature of the aqueous phase in the reactor reached 70°C, the organic phase was charged into the reactor using a narrow-mouthed glass funnel. The temperature of the reaction vessel decreased with the addition of the organic phase. The PolyStat temperature program was started and the reaction vessel was heated from 60 to 77° C. over 30 minutes, heated from 77 to 80° C. over 30 minutes, held at 80° C. for 960 minutes, and cooled to 20° C. over 60 minutes.

Workup: Marked the reaction volume level in the reactor. The stirring of the overhead stirrer was stopped, the residual liquid was sucked from the reactor, and the reactor was filled with room temperature ultrapure water. The overhead stirrer agitation was resumed and the slurry was heated to 70° C. as quickly as possible. After 30 minutes, the stirring was stopped and the residual liquid was siphoned off. The polymer beads were washed 5 times in this manner. For the final wash, the slurry temperature was cooled to room temperature. After the final water wash, the polymer beads were washed with 99% isopropyl alcohol (IPA) in the same manner. The 99% IPA was siphoned and replaced with 70% IPA before transferring the slurry to a clean 4 L glass vessel. If necessary, the polymer is steam stripped in a stainless steel tube for 8 hours, rewetted with 70% IPA, and transferred into pure water to obtain only the portion of the beads with a diameter of 300-600 μm, unless otherwise noted. The powder was sieved for sieving and dried at 100° C. until no weight loss was observed on drying.

Cumulative pore volume data measured by nitrogen desorption isothermal and mercury intrusion porosimetry for polymers CY14175 and CY15077, respectively, are shown in Tables III and IV below, respectively.

Example 2. Removal of Soluble PD-L1 (sPD-L1) from Bovine Whole Blood CytoSorb is a specific adsorbent manufactured by CytoSorbents, Inc. that meets the above polymer criteria. Data from a benchtop evaluation (Fig. 1) show that CytoSorb can remove soluble PD-L1 (sPD-L1) from bovine whole blood. In this study, two doses of CytoSorb were evaluated. Two volumes of 60 mL and 120 mL were evaluated. After 6 hours, CytoSorb 60 mL removed 49% of the starting sPD-L1 concentration and CytoSorb 120 mL removed 76% of the starting sPD-L1 concentration. Controls (placebo, no CytoSorb) were evaluated concurrently with each CytoSorb experiment. Each group was repeated three times (n=3).

Example 3. Removal of Anti-Inflammatory Cytokines by Adsorbent Therapy Excess anti-inflammatory cytokines cause immunosuppression. Removal of these substances by sorbents may restore immunosuppression. Table V below summarizes the broad spectrum and robust in vitro removal of anti-inflammatory cytokines by CytoSorb.

Example 4 Removal of Inflammatory Cytokines and Inflammatory Mediators As mentioned above, overproduction of inflammatory mediators, such as inflammatory cytokines, causes, for example, apoptosis of immune effector cells, and promotes infection-fighting leukocytes into the blood vessels of healthy organs. It causes upregulation of endothelial cell adhesion molecules, which aberrantly sequester on the endothelium and away from sites of infection, and rebound anti-inflammatory responses, also called compensatory anti-inflammatory response syndrome (CARS), paradoxically leading to immunosuppression. Adsorbent therapy aims to reduce these inflammatory mediators and reduce the risk of these immunosuppressive complications.

The following data demonstrate that CytoSorb, a commercialized adsorption therapy, can remove prototypes of several inflammatory cytokines in which toxins play an important role.

FIG. 2 shows that the inflammatory cytokines IL-6 (FIG. 2B), MCP-1α (FIG. 2C), tumor necrosis factor (TNF-α, (FIG. 2D)) and interferon-γ (IFN-γ, FIG. 2A) Efficient removal by CytoSorb.

Figure 3. Inflammatory mediators such as damage-associated molecular pattern (DAMPS) C5a (Figure 3A), HMGB-1 (Figure 3B), procalcitonin (Figure 3C), and S100-A8 (Figure 3D) are efficiently removed by CytoSorb. indicates that

FIG. 4 shows that inflammatory mediators such as pattern-associated molecular pattern (PAMPS) α-toxin (FIG. 4A), SpeB (FIG. 4B), TSST-1 (FIG. 4C) are efficiently removed by CytoSorb.

These experiments were performed in vitro, where purified inflammatory proteins were spiked into a 3.8% citrate whole blood recirculating system, blue are cartridges containing CytoSorb polymer (13:3 v/v blood to polymer); Red, sham (no polymer) cartridges were pumped with blood at flow rates of 20-140 mL/min. A rapid decrease in these inflammatory mediators can be seen in the graph below. In human immunosuppressive treatment with CytoSorb, continuous use of CytoSorb at a flow rate of 150-400 mL/min in an extracorporeal CRRT circuit, with replacement of a new CytoSorb device every 8-24 hours, reduced these inflammatory mediators and One would expect an improvement in immune reactivity.

Reference Gruda, et al. PLOS ONE 2018;13(1):e0191676.

Example 5 Evaluation of Immune System Function Before and After Adsorbent Treatment To demonstrate the effects of sorbent treatment on immunosuppression and immunoparalysis, blood samples were collected from patients before and after sorbent treatment and analyzed for a number of parameters. compare.

The ImmuKnow® Test (Eurofins Viracor; Missouri, USA) is a commercially available assay that uses an ATP luciferase assay to measure ATP production in response to PHA stimulation of CD4+ T cells isolated from peripheral blood. Immunolevels ≦225 ng/mL represent a low immune cell response, 226-524 mg/mL a moderate immune response, and ≧525 ng/mL a high immune cell response. [http://portals. cleveland clinic. org/portals/66/PDF/TechBriefs/TB_ImmuneFunctionAssay. pdf]

The effect of CytoSorb on immunosuppression as measured by the Immuknow test is exemplified by two septic patients receiving CytoSorb for 7 consecutive days for 6 hours per day in an extracorporeal circuit using CRRT. This data is summarized in Table VI below. Immunoassays were performed before the first treatment on day 1 and then on days 3, 5 and 7. The first patient was a 59 year old male with pneumonia, renal failure and septic shock. The second patient was a 72-year-old woman who had aspiration pneumonia and septic shock.

Initial ImmuKnow values on day 1 before CytoSorb treatment in these patients confirmed immunosuppression with low immune responses. As CytoSorb treatment progressed, ImmuKnow values increased, indicating that CD4+ T cells became more responsive to PHA stimulation, indicating a reversal of immunosuppression.

Example 6 Stimulation of Immune Cell Activation After Adsorbent Treatment of Patients or Patient Blood Increased proliferation of regulatory T cells (T- _regs ) can be achieved through transdifferentiation of _H1 helper T cells or de novo differentiation from naive T cells [Battaglia 06, Gutcher 07]. Regulatory T cells function to downregulate the activity of proximal and distal effector T cells through direct cell-to-cell contact inhibition and secreted cytokines (eg, IL-10 and TGF-β) [ Gregory 12]. IL-10 directly inhibits the production of inflammatory cytokines IL-2, IFNγ, GM-CSF by effector T cells and shifts the adaptive immune response from an active to a suppressive state [Yudoh00].

The treatment proposed in this patent directly removes excess levels of anti-inflammatory cytokines and other soluble secreted immunosuppressive factors in patients who are severely immunosuppressed as a result of cytokine storms resulting from various diseases, including sepsis. It is. The effects of this treatment can be evaluated by quantifying the ratio of circulating activated effector T cells to regulatory T cells in a humanized in vivo immunosuppressive animal model [Jespersen17, Wu13]. Immunosuppressed individuals usually have more regulatory T cells and fewer activated effector cells. Different T cell lineages can be mapped by antibody staining for unique surface or intracellular markers present in each T cell type and enumerated by fluorescence-assisted cell sorting (FACS) using flow cytometry or gating approaches. . All T cells can be distinguished from other leukocyte classes by staining for CD3, a component of the surface T cell receptor. To distinguish between CD4 ⁺ helper T cells and CD8 ⁺ cytotoxic T cells, secondary stainings specific for surface CD4 and CD8 can be applied. Finally, tertiary staining for, for example, surface CD69, CD25, HLA-DR, and CD122 can be applied to distinguish between activated and non-activated T cells; Staining for CD152 (CTLA4) and intracellular Foxp3 can also be included [Bajnok17, Mousset19]. After treatment, systemic levels of major anti-inflammatory immunosuppressive factors are reduced, resulting in markedly reduced proliferation and activity of regulatory T cells, and ultimately attenuated suppression of effector T cell activation. is expected to allow for increased proliferation of effector cells of This phenomenon can be easily visualized using the methods described above, whereby the gating output of flow cytometry shows more effector T cells and less regulatory T cells after treatment. It could be demonstrated that there is a clear shift in T cell populations such that

References Gregori, Silvia, Kevin S.; Goudy, and Maria Grazia Roncarolo. "The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells." Frontiers in immunology 3 (2012): 30.
Yudoh, Kazuo, et al. "Reduced expression of the regulatory CD4+ T cell substrate is related to Th1/Th2 balance and disease severity in rheumatoid arthritis."Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 43.3 (2000): 617-627.
Battaglia, Manuela, et al. "Tr1 cells: from discovery to their clinical application."Seminars in immunology. Vol. 18. No. 2. Academic Press, 2006.
Gutcher, Ilona, and Burkhard Becher. "APC-derived cytokines and T cell polarization in autoimmune inflammation." The Journal of clinical investigation 117.5 (2007): 1119-1127.
Mousset, Charlotte M.; , et al. "Comprehensive phenotyping of T cells using flow cytometry." Cytometry Part A 95.6 (2019): 647-654.
Bajnok, Anna, et al. "The distribution of activation markers and selections on peripheral T lymphocytes in preclampsia." Mediators of information 2017 (2017).
Jespersen, Henrik, et al. "Clinical responses to adaptive T-cell transfer can be modeled in an autologous immune-humanized mouse model." Nature communications 8.1 (2017): 1-10.
Wu, Douglas C.; , et al "Ex vivo expanded human regulation T cells can prolong survival of a human islet allograft in a humanized mouse model."Transplantation 96.8 (2013 ): 707.

Example 7 Measurement of Reversal of Immune Cell Function and Immunosuppression or Other Methods Before and After Adsorbent Treatment White blood cell counts, as measured by whole blood counts and differential white blood cell counts, are crude measures of immune function and immune cell depletion. . In neutropenic patients, sorbent therapy may alleviate immunosuppression, promote cell growth and differentiation, and lead to immune cell expansion or repopulation.

Activation levels of peripheral blood mononuclear cells (PBMC such as T-cells, B-cells, natural killer cells, monocytes) were determined by fluorescence-activated cell sorting (FACS) based on cell surface markers of cell activation such as HLA-DR. ) (see Example 6). Intracellular metabolic activity can also be detected by FACS. For example, exposure of activated neutrophils to phorbol myristate acetate (PMA) results in an oxidative burst (eg, hydrogen peroxide) via NADPH oxidase activity, which can be detected by FACS using dihydrorhodamine. It is possible. After adsorbent treatment, a higher percentage of activated PBMCs or neutrophils is expected by FACS analysis.

Immune function assays also assess the ability of purified PBMCs and PBMCs in whole blood to respond to various stimuli. One example is a cell proliferation assay in which PBMCs are exposed to active agents such as phytohemagglutinin (PHA), pokeweed mitogen (PWM), tetanus toxoid, and the like. For lymphocytes, this assay is also called lymphocyte proliferation test or lymphocyte transformation test. Immunoparalyzed cells do not proliferate or proliferate slowly, activated cells proliferate faster and increase in cell number. Other methods of detecting cell proliferation include, but are not limited to, cell cycle analysis, DNA histograms, co-culture cytotoxicity, and other techniques that detect the proportion of replicating or functional cells. Adsorbent treatment is expected to increase this percentage. In another example, PBMCs are stimulated with activating agents that increase transcriptional or metabolic activity, including substances such as PHA as in Example 4, or lipopolysaccharide endotoxin. In the latter, anergy, which includes PHA as in Example 5, and other activators. For example, stimulation with endotoxin in normal or activated immune cells causes these cells to produce immunoassayable cytokines. Cytokine production is low in quiescent or immunosuppressive cells and increases during and after adsorbent treatment. An example of sorbent treatment is the repeated recirculation of blood outside the body, through a temporary dialysis catheter placed in a major vein, through a sorbent cartridge, and back into the body.

Example 8: How to Reduce Functional Immunosuppression by Reducing Abnormal Sequestration of Leukocytes and Improving Leukocyte Targeting to Areas of Injury and Infection Cell-mediated immunity is important in response to injury and infection . For example, a genetic disorder called leukocyte adhesion deficiency type I is known, in which leukocytes are unable to bind to the walls of blood vessels and invade sites of infection, resulting in functional immunosuppression, leading to life-threatening bacterial and bacterial infections. Become highly susceptible to fungal infections.

In sepsis, excessive inflammation and cytokine overexpression, called cytokine storm, lead to global upregulation of endothelial cell adhesion molecules, leukocyte adhesion molecules, and integrins, leading to unwanted binding of leukocytes to the endothelium of blood vessels throughout the body. There is This abnormal sequestration of leukocytes reduces the availability of immune cells to fight injury or infection at the true site of infection or injury. This process also interferes with the normal ability of leukocytes to locate the true site of infection or injury through normal processes of leukocyte rolling, adhesion and endothelial migration. Activated leukocytes are unable to reach the site of injury or infection, resulting in functional immunosuppression.

For example, extracorporeal adsorption therapy to reduce circulating inflammatory cytokines and mediators in sepsis reduces global expression of endothelial cell adhesion molecules, reduces abnormal leukocyte margins, and increases the number of leukocytes at the site of infection. and reduced bacterial counts (or improved source control), partial or complete ablation of this functional immunosuppression with reduced leukocyte infiltration and cell-mediated damage in uninfected organs and tissues. .

Aspects of Disclosure A first aspect of the present invention is a method of treating immunosuppression, allergy, or immunoparalysis by attenuation by removal of inflammatory and/or anti-inflammatory mediators and/or checkpoint inhibitor proteins in a subject. and treating the subject with a therapeutically effective amount of the porous biocompatible polymeric adsorbent.

A second aspect of the present invention is according to the first aspect, wherein said adsorbent comprises a pore size in the range of about 50 Å to about 3000 Å and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer related to the method.

A third aspect of the present invention is the adsorbent of the first, wherein said adsorbent comprises a pore size in the range of about 50 Å to about 40,000 Å and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. It relates to a method according to aspects.

A fourth aspect of the invention relates to the method of any one of the first to third aspects, wherein said adsorbent is administered extracorporeally.

A fifth aspect of the present invention is any of the first to third aspects, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method according to any one.

A sixth aspect of the present invention is the adsorbent according to the third aspect, wherein the ratio of the pore volume of 50 Å to 40,000 Å (pore diameter) to the pore volume of 1,000 Å to 10,000 Å (pore diameter) of the adsorbent is less than 2:1. A method according to an aspect.

A seventh aspect of the invention relates to a method according to any of the previous aspects, wherein said adsorbent is produced using at least one cross-linking agent and at least one monomer.

An eighth aspect of the present invention relates to the method according to the seventh aspect, wherein said monomers are divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate , cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinyl Sulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate , pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide. Including above.

A ninth aspect of the present invention relates to the method according to the seventh aspect or the eighth aspect, wherein the cross-linking agent is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate. , trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetra one or more of acrylates, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide.

A tenth aspect of the present invention is any one of the seventh to ninth aspects, wherein said adsorbent is additionally prepared utilizing one or both of at least one dispersant and at least one porogen It relates to the described method.

An eleventh aspect of the present invention is any one of the first to tenth aspects, wherein said adsorbent comprises a biocompatible and blood compatible outer coating covalently bonded to said adsorbent by free radical graft polymerization. relates to the method described in

A twelfth aspect of the invention relates to the method of any one of the first to eleventh aspects, wherein said adsorbent is administered prior to administration of supportive care.

A thirteenth aspect of the invention relates to the method of any one of the first through seventeenth aspects, wherein the adsorbent is administered concurrently with the administration of supportive care.

A fourteenth aspect of the invention relates to the method of any one of the first to eleventh aspects, wherein said adsorbent is administered after administration of supportive care.

A fifteenth aspect of the present invention is thirteenth, wherein said supportive therapy comprises administration of an immunotherapeutic agent selected from one or more of checkpoint inhibitors, monoclonal antibodies, and bispecific T cell engagers. 15. The method according to any one of aspects -14.

A sixteenth aspect of the present invention relates to the method of any one of the first to eleventh aspects, wherein administration of said adsorbent reduces the severity of immunoparalysis.

A seventeenth aspect of the present invention relates to the method of any one of the first to eleventh aspects, wherein administration of said adsorbent increases HLA-DR expression or function.

An eighteenth aspect of the present invention relates to the method of any one of the first to eleventh aspects, wherein administration of the sorbent reduces damage to the body caused by a hyperinflammatory response, thereby A method for reducing the risk of immune paralysis.

A nineteenth aspect of the invention relates to the method of any one of aspects 1-11, wherein administration of said adsorbent reduces exhaustion of T cells or other immune cells.

A twentieth aspect of the present invention relates to any one of items 1-11, wherein administration of said adsorbent removes one or more of a) cytokines and b) soluble ligands from said subject's body fluid/saline. A method according to any one of the aspects of

A twenty-first aspect of the present invention relates to the method of any one of the first to eleventh aspects, wherein administration of said adsorbent results in removal of inflammatory mediators.

A twenty-second aspect of the present invention relates to the method of any one of the first to eleventh aspects, wherein administration of said adsorbent results in the reduction of one or more checkpoint inhibitory proteins and/or their soluble counterparts. objects are removed.

A twenty-third aspect of the present invention is according to any one of the first to eleventh aspects, wherein administration of the adsorbent results in restoration of some or all of the functions of T cells or other immune cells. concerning the method of

A twenty-fourth aspect of the present invention, wherein said soluble ligand is one or more of sPD-L1, sPD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. A method according to an aspect.

A twenty-fifth aspect of the present invention is according to the twentieth aspect, wherein said cytokine comprises one or more of an interleukin, chemokine, interferon, lymphokine, tumor growth factor, or tumor necrosis factor family member. It relates to such a method.

The twenty-sixth aspect of the present invention is any one of the first to twenty-fifth aspects, wherein said adsorbent comprises residues of one or more of divinylbenzene and ethylvinylbenzene, styrene, and ethylstyrene monomers. relates to the method described in

A twenty-seventh aspect of the invention relates to a method of reducing sepsis and inflammation-related T-cell dysfunction in a subject, comprising treating said subject with a therapeutically effective amount of a porous biocompatible polymeric adsorbent. It is.

A twenty-eighth aspect of the present invention according to the twenty-seventh aspect, wherein said adsorbent comprises a pore size in the range of about 50 Å to about 3000 Å and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer It is about the method.

A twenty-ninth aspect of this invention is the A method according to an embodiment.

A thirtieth aspect of the invention relates to the method of any one of aspects 27-29, wherein said adsorbent is administered extracorporeally.

The 31st aspect of the present invention is any of 27th to 29th, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. It relates to a method according to one aspect.

A thirty-second aspect of the present invention relates to the method according to the twenty-ninth aspect, wherein the adsorbent has a total pore volume of 0.5 cc/g to 5.0 cc/g dry with pore diameters ranging from 50 Å to 40,000 Å. comprising a pore structure larger than that of the adsorbent, wherein the ratio of the pore volume of 50 Å to 40,000 Å (pore diameter) to the pore volume of 1,000 Å to 10,000 Å (pore diameter) of said adsorbent is 2: less than 1

A thirty-third aspect of the present invention relates to the method of any one of aspects 27-32, wherein the adsorbent is produced using at least one cross-linking agent and at least one monomer. .

A thirty-fourth aspect of the present invention relates to the method according to the thirty-third aspect, wherein said monomers are divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate , cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinyl Sulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate , pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, vinylylformamide, and mixtures thereof including.

A thirty-fifth aspect of the present invention relates to the method according to the thirty-third or thirty-fourth aspect, wherein the cross-linking agent is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate , trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane dimethacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetra acrylates, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, divinylformamide.

A thirty-sixth aspect of the present invention is a method of treating immunoparalysis in a subject in need thereof comprising contacting a physiological fluid of said subject with a porous biocompatible polymeric adsorbent, said method comprising: removes inflammatory mediators, and/or anti-inflammatory mediators, and/or checkpoint proteins.

A thirty-seventh aspect of the present invention according to the thirty-sixth aspect, wherein said adsorbent comprises a pore size in the range of about 50 Å to about 3000 Å and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer Regarding the method.

A thirty-eighth aspect of the present invention is the A method according to an embodiment.

A thirty-ninth aspect of the present invention, wherein the contacting step comprises administering the adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. It relates to a method according to any one of aspects 36-38.

A fortieth aspect of the present invention relates to the method of any one of aspects thirty-six to thirty-eight, wherein said contacting step comprises administering said adsorbent extracorporeally.

A forty-first aspect of the invention is a method of treating an immunodeficiency in a subject in need thereof, comprising administering to said subject a porous biocompatible polymeric adsorbent, said administering comprising said adsorbent A method of contacting an agent with a physiological fluid of said subject.

A forty-second aspect of the present invention is according to the fortieth aspect, wherein said adsorbent comprises a pore size in the range of about 50 Å to about 3000 Å and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer The method.

A forty-third aspect of the present invention relates to the method according to the fortieth aspect, wherein said adsorbent comprises pore sizes ranging from about 50 Å to about 40,000 Å and from about 0.5 cc/g to about 5 cc/g dry polymer. of pore volumes.

A forty-fourth aspect of the present invention relates to the method of any one of the forty-first through forty-third aspects, wherein the physiological fluid is blood.

A forty-fifth aspect of the present invention relates to the method of any one of the forty-first to forty-fourth aspects, wherein the adsorbent is administered extracorporeally.

The forty-sixth aspect of the present invention is any of the forty-first to forty-fourth aspects, wherein said adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method according to any one of

A forty-seventh aspect of the invention relates to a method of treating immunoparalysis in a subject in need thereof, comprising the step of providing said subject with a porous biocompatible polymeric adsorbent.

A forty-eighth aspect of the present invention relates to the method of the forty-seventh aspect, wherein the adsorbent has a pore size in the range of about 50 Å to about 3000 Å and pores of about 0.5 cc/g to about 3 cc/g dry polymer. Including volume.

A forty-ninth aspect of the present invention relates to the method of the forty-seventh aspect, wherein the adsorbent comprises a pore size ranging from about 50 Å to about 40,000 Å and a density of about 0.5 cc/g to about 5 cc/g dry polymer. Includes pore volume.

A fiftieth aspect of the invention relates to the method of any one of the forty-seventh to forty-ninth aspects, wherein administration of the adsorbent reduces the severity of immunoparalysis, immunosuppression, or anergy. .

A fifty-first aspect of the present invention relates to the method of any one of the forty-seventh to forty-ninth aspects, wherein administration of the adsorbent reduces damage to the body caused by a hyperinflammatory response, Thereby reducing the patient's risk of immunoparalysis, immunosuppression, or anergy.

A fifty-second aspect of the invention pertains to the method of any one of the forty-seventh to forty-ninth aspects, wherein administration of the adsorbent reduces T cell exhaustion.

The fifty-third aspect of the present invention is the forty-seventh aspect, wherein said adsorbent results in the removal of one or more of a) cytokines and b) soluble ligands from said subject's body fluid/saline. The method according to any one of the -49th aspects.

A fifty-fourth aspect of the present invention pertains to the method of any one of the forty-seventh to forty-ninth aspects, wherein the adsorbent effects removal of an inflammatory mediator.

A fifty-fifth aspect of the invention pertains to the method of any one of the forty-seventh to forty-ninth aspects, wherein the adsorbent effects removal of checkpoint inhibitor proteins.

A fifty-sixth aspect of the invention relates to the method of any one of the forty-seventh to forty-ninth aspects, wherein said adsorbent results in partial or complete restoration of T cell function.

The fifty-seventh aspect of the present invention is the fifty-third A method according to an aspect.

A fifty-eighth aspect of the invention relates to a method according to the fifty-third aspect, wherein the cytokine comprises one or more of an interleukin, chemokine, interferon, lymphokine, tumor growth factor, or member of the tumor necrosis factor family. .

A fifty-ninth aspect of the present invention relates to the method of any one of the forty-seventh to fifty-eighth aspects, wherein the adsorbent is administered extracorporeally.

The 60th aspect of the invention is any of the 47th to 58th aspects, wherein said adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method according to any one of

A sixty-first aspect of the invention is a method of treating sepsis and/or inflammation-associated T-cell or immune cell dysfunction in a subject in need thereof, wherein said subject's physiological fluid comprises a porous biocompatible polymer It relates to a method of contact with an adsorbent.

A sixty-second aspect of the present invention relates to the method according to the sixtieth first aspect, wherein said adsorbent has a pore size in the range of about 50 Å to about 3000 Å and a concentration of about 0.5 cc/g to about 3 cc/g dry polymer. Includes pore volume.

A sixty-third aspect of the present invention relates to the method according to the sixty-first aspect, wherein said adsorbent comprises pore sizes ranging from about 50 Å to about 40,000 Å and fine particles of about 0.5 cc/g to about 5 cc/g dry polymer. Includes pore volume.

The sixty-fourth aspect of the present invention, wherein said contacting step comprises administering said adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method according to any one of the 60 first to sixth third aspects.

A sixty-fifth aspect of the present invention relates to the method of any one of the sixty-first to sixty-third aspects, wherein the contacting step comprises administering the adsorbent extracorporeally.

A sixty-sixth aspect of the invention is a method of treating T cell or other immune cell dysfunction associated with sepsis and/or inflammation in a subject in need thereof, comprising: to said subject, said administering comprising contacting said sorbent with physiological fluids of said subject.

A sixty-seventh aspect of the present invention relates to the method of any one of the forty-seventh through sixty-sixth aspects, wherein the physiological fluid is blood.

A sixty-eighth aspect of the invention is a method of treating sepsis and/or inflammation-associated T-cell dysfunction in a subject in need thereof comprising providing said subject with a porous biocompatible polymeric adsorbent. Regarding the method of containing.

The sixty-ninth aspect of the present invention relates to the method of any one of the sixty-sixth through sixty-eighth aspects, wherein the adsorbent has a pore size ranging from about 50 Å to about 3000 Å and a g to about 3 cc/g dry polymer pore volume.

The 70th aspect of the present invention is the 66th A method according to any one of aspects through the sixty-eighth aspect.

The seventy-first aspect of the present invention is the sixty-sixth aspect, wherein the contacting step comprises administering the adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method according to any one of aspects 1 through 68.

A seventy-second aspect of the invention relates to the method of any one of the sixty-sixth through sixty-eighth aspects, wherein the contacting step comprises administering the adsorbent extracorporeally.

A seventy-third aspect of the present invention relates to the method according to the seventieth aspect, wherein the adsorbent has a total pore volume of 0.5 cc/g to 5.0 cc/g with pore sizes ranging from 50 Å to 40,000 Å. comprising a pore structure larger than that of the dry adsorbent and a ratio of pore volume of 50 Å to 40,000 Å (pore diameter) to pore volume of 1,000 Å to 10,000 Å (pore diameter) of said adsorbent of 2 : less than 1.

A seventy-fourth aspect of the present invention relates to the method of any one of the sixty-sixth through seventy-third aspects, wherein the sorbent is prepared using at least one cross-linking agent and at least one monomer. It is.

A seventy-fifth aspect of the present invention relates to the method according to the seventy-fourth aspect, wherein the monomer is divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, acrylic acid Octyl, cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyl toluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, Divinyl sulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol tri one of acrylates, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide or more.

A seventy-sixth aspect of the present invention relates to the method according to the seventy-fourth or seventy-fifth aspect, wherein the cross-linking agent is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, or trimethylol. propane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane dimethacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, one or more of pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide including.

A seventy-seventh aspect of the present invention is a method according to the seventy-fourth or seventy-fifth aspect, wherein said adsorbent is additionally prepared utilizing one or both of at least one dispersant and at least one porogen. Regarding.

The seventy-eighth aspect of this invention is any of the sixty-sixth through seventy-third aspects, wherein said adsorbent comprises a biocompatible and blood-compatible outer coating covalently bonded to the adsorbent by free radical graft polymerization. or relates to the method according to one item.

The seventy-ninth aspect of the invention pertains to the method of any one of the sixty-sixth through seventy-third aspects, wherein the adsorbent is administered prior to administration of supportive care.

The eightieth aspect of the invention pertains to the method of any one of the sixtieth through seventieth aspects, wherein the adsorbent is administered concurrently with the administration of supportive care.

The eighty-first aspect of the invention pertains to the method of any one of the sixty-sixth through seventieth aspects, wherein the adsorbent is administered after administration of supportive care.

The eighty-second aspect of the invention is the supportive therapy comprising administration of an immunotherapeutic agent selected from one or more of checkpoint inhibitors, monoclonal antibodies, and bispecific T-cell engagers. 80 relates to a method according to the first aspect.

The 83rd aspect of this invention is any of the 66th to 70th aspects, wherein said adsorbent comprises residues of one or more of divinylbenzene and ethylvinylbenzene, styrene, and ethylstyrene monomers. 1. It relates to the method of Claim 1.

The eighty-fourth aspect of the invention is that administration for said adsorbent reduces endothelial sequestration of leukocytes and/or increases the presence of leukocytes in areas of infection or injury and/or reduces infection and/or A method according to any one of the first to twenty-sixth aspects, which results in improved healing.

Claims (84)

A method of treating immunosuppression, allergy, or immunoparalysis by attenuation by removal of inflammatory and/or anti-inflammatory mediators and/or checkpoint inhibitor proteins in a subject, comprising: a therapeutically effective amount of a porous biomaterial comprising: treating a subject with a polymeric sorbent. The method of claim 1, wherein the adsorbent comprises a pore size in the range of about 50 Å to about 3000 Å and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. The method of claim 1, wherein said adsorbent comprises a pore size in the range of about 50 A to about 40,000 A and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. the method of. The method of any one of claims 1-3, wherein the adsorbent is administered extracorporeally. The method of any one of claims 1-3, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. . 4. The method of claim 3, wherein the ratio of 50 Å to 40,000 Å (pore diameter) pore volume to 1,000 Å to 10,000 Å (pore diameter) pore volume of the adsorbent is less than 2:1. The method of any one of claims 1-6, wherein the adsorbent is produced using at least one cross-linking agent and at least one monomer. 8. The method of claim 7, wherein the monomer is divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate. , ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, Trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipenta comprising one or more of erythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide. 9. The method of claim 7 or claim 8, wherein the cross-linking agent is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane. Triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipenta comprising one or more of erythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide. The method of any one of claims 7-9, wherein the adsorbent is additionally prepared utilizing one or both of at least one dispersant and at least one porogen. The method of any one of claims 1-10, wherein the adsorbent comprises a biocompatible and blood compatible outer coating covalently bonded to the adsorbent by free radical graft polymerization. 12. The method of any one of claims 1-11, wherein the adsorbent is administered prior to administration of supportive care. 12. The method of any one of claims 1-11, wherein the adsorbent is administered concurrently with the administration of supportive care. 12. The method of any one of claims 1-11, wherein the adsorbent is administered after administration of supportive care. 15. The method of any of claims 12-14, wherein said supportive therapy is administration of an immunotherapeutic agent selected from one or more of checkpoint inhibitors, monoclonal antibodies, and bispecific T cell engagers A method, including 12. The method of any one of claims 1-11, wherein administration of the sorbent reduces the severity of immunoparalysis. 12. The method of any one of claims 1-11, wherein administration of the sorbent increases HLA-DR expression or function. 12. The method of any one of claims 1-11, wherein administration of the sorbent reduces damage to the body caused by a hyperinflammatory reaction, thereby reducing the risk of immune paralysis in the patient. . 12. The method of any of claims 1-11, wherein administration of the adsorbent reduces exhaustion of T cells or other immune cells. 12. The method of any one of claims 1-11, wherein administration of the sorbent removes one or more of a) cytokines and b) soluble ligands from the body fluid/saline of the subject. done, method. 12. The method of any one of claims 1-11, wherein administration of the sorbent results in removal of inflammatory mediators. 12. The method of any one of claims 1-11, wherein administration of the sorbent removes one or more checkpoint inhibitor proteins and/or their soluble counterparts. 12. The method of any one of claims 1-11, wherein administration of the adsorbent results in restoration of some or all of T-cell or other immune cell function. 21. The method of claim 20, wherein the soluble ligand is one or more of sPD-Ll, sPD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. 21. The method of claim 20, wherein the cytokine comprises one or more of members of the interleukins, chemokines, interferons, lymphokines, tumor growth factors, or tumor necrosis factor families. 26. The method of any one of claims 1-25, wherein the adsorbent comprises residues of one or more of divinylbenzene and ethylvinylbenzene, styrene, and ethylstyrene monomers. A method of reducing sepsis and inflammation-associated T-cell dysfunction in a subject, comprising treating said subject with a therapeutically effective amount of a porous biocompatible polymeric adsorbent. 28. The method of claim 27, wherein the adsorbent comprises a pore size in the range of about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. 28. The method of claim 27, wherein the adsorbent comprises a pore size ranging from about 50 Å to about 40,000 Å and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. 30. The method of any one of claims 27-29, wherein the sorbent is administered extracorporeally. 30. The method of any one of claims 27-29, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. . The method of claim 29, wherein the adsorbent has a pore structure with a total pore volume greater than 0.5 cc/g to 5.0 cc/g dry adsorbent with pore sizes ranging from 50 Å to 40,000 Å. wherein the ratio of 50 Å to 40,000 Å (pore diameter) pore volume to 1,000 Å to 10,000 Å (pore diameter) pore volume of said adsorbent is less than 2:1. The method of any one of claims 27-32, wherein the adsorbent is manufactured using at least one cross-linking agent and at least one monomer. 34. The method of claim 33, wherein the monomer is divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate. , ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, Trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipenta erythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, vinylylformamide, and mixtures thereof. 35. The method of claim 33 or claim 34, wherein the crosslinker is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane Triacrylate, trimethylolpropane dimethacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipenta comprising one or more of erythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, divinylformamide. 1. A method of treating immunoparalysis in a subject in need thereof comprising contacting a physiological fluid of said subject with a porous biocompatible polymeric adsorbent, said method comprising an inflammatory mediator and/or anti-inflammatory agent. A method of removing inflammatory mediators and/or checkpoint proteins. 37. The method of claim 36, wherein the adsorbent comprises a pore size in the range of about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. 37. The method of claim 36, wherein the adsorbent comprises a pore size ranging from about 50 A to about 40,000 A and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. 39. The method of any one of claims 36-38, wherein the contacting step includes administering the adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method comprising the step of administering. 39. The method of any one of claims 36-38, wherein the contacting step comprises administering the adsorbent extracorporeally. A method of treating an immunodeficiency in a subject in need thereof, comprising:
administering to said subject a porous biocompatible polymeric adsorbent;
The method wherein said administering contacts said sorbent with physiological fluids of said subject. 42. The method of claim 41, wherein the adsorbent comprises a pore size in the range of about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. 42. The method of claim 41, wherein the adsorbent comprises a pore size ranging from about 50 A to about 40,000 A and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. 44. The method of any one of claims 41-43, wherein the physiological fluid is blood. 45. The method of any one of claims 41-44, wherein the sorbent is administered extracorporeally. 45. The method of any one of claims 41-44, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method of treating immunoparalysis in a subject in need thereof, comprising providing said subject with a porous biocompatible polymeric adsorbent. 48. The method of claim 47, wherein the adsorbent comprises a pore size in the range of about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. 48. The method of claim 47, wherein the adsorbent comprises a pore size ranging from about 50 A to about 40,000 A and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. 50. The method of any one of claims 47-49, wherein administration of the sorbent reduces the severity of immunoparalysis, immunosuppression, or anergy. 50. The method of any one of claims 47-49, wherein administration of the sorbent reduces damage to the body caused by a hyperinflammatory reaction, thereby reducing the patient's immunoparalysis, immunosuppression, or anergy. method of reducing the risk of 50. The method of any one of claims 47-49, wherein administration of the adsorbent reduces T cell exhaustion. 50. The method of any one of claims 47-49, wherein the adsorbent removes one or more of a) cytokines and b) soluble ligands from the body fluid/saline of the subject. method. 50. The method of any one of claims 47-49, wherein the adsorbent effects removal of inflammatory mediators. 50. The method of any one of claims 47-49, wherein the adsorbent effects removal of checkpoint inhibitor proteins. 50. The method of any one of claims 47-49, wherein the adsorbent results in partial or complete restoration of T cell function. 54. The method of claim 53, wherein the soluble ligand is one or more of sPD-L1, sPD-L2, sMICA, sULBP2, sFasL, sCTLA-4, MHC class II, and sCD40L. 54. The method of claim 53, wherein the cytokine comprises one or more of members of the interleukins, chemokines, interferons, lymphokines, tumor growth factors, or tumor necrosis factor families. 59. The method of any one of claims 47-58, wherein the sorbent is administered extracorporeally. 59. The method of any one of claims 47-58, wherein the adsorbent is administered intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method of treating sepsis and/or inflammation-related T cell or immune cell dysfunction in a subject in need thereof, comprising contacting a physiological fluid of said subject with a porous biocompatible polymeric adsorbent. 62. The method of claim 61, wherein the adsorbent comprises a pore size ranging from about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. 62. The method of claim 61, wherein the adsorbent comprises a pore size in the range of about 50 A to about 40,000 A and a pore volume of about 0.5 cc/g to about 5 cc/g dry polymer. 64. The method of any one of claims 61-63, wherein the contacting step includes administering the adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. A method comprising the step of administering. 64. The method of any one of claims 61-63, wherein the contacting step comprises administering the adsorbent extracorporeally. A method of treating T cell or other immune cell dysfunction associated with sepsis and/or inflammation in a subject in need thereof comprising administering to said subject a porous biocompatible polymeric adsorbent. ,
The method wherein administering comprises contacting the adsorbent with physiological fluids of the subject. 67. The method of any one of claims 47-66, wherein the physiological fluid is blood. A method of treating sepsis and/or inflammation-related T-cell dysfunction in a subject in need thereof, comprising providing said subject with a porous biocompatible polymeric adsorbent. 69. The method of any one of claims 66-68, wherein the adsorbent has a pore size in the range of about 50 A to about 3000 A and a pore volume of about 0.5 cc/g to about 3 cc/g dry polymer. including, method. 69. The method of any one of claims 66-68, wherein the adsorbent has a pore size ranging from about 50 A to about 40,000 A and a pore size of about 0.5 cc/g to about 5 cc/g dry polymer. Methods, including volume. 69. The method of any one of claims 66-68, wherein the contacting step administers the adsorbent intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, orally, rectally, topically, or intranasally. a method comprising the step of 69. The method of any one of claims 66-68, wherein the contacting step comprises administering the adsorbent extracorporeally. 71. The method of claim 70, wherein the adsorbent has a pore structure with a total pore volume greater than 0.5 cc/g to 5.0 cc/g dry adsorbent for pore sizes ranging from 50 Å to 40,000 Å. wherein the ratio of 50 Å to 40,000 Å (pore diameter) pore volume to 1,000 Å to 10,000 Å (pore diameter) pore volume of said adsorbent is less than 2:1. 74. The method of any one of claims 66-73, wherein the adsorbent is manufactured using at least one cross-linking agent and at least one monomer. 75. The method of claim 74, wherein the monomer is divinylbenzene and ethylvinylbenzene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate. , ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, Trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipenta comprising one or more of erythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide. 76. The method of claim 74 or claim 75, wherein the crosslinker is divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane Triacrylate, trimethylolpropane dimethacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol, tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipenta comprising one or more of erythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, and divinylformamide. 76. The method of claim 74 or claim 75, wherein the adsorbent is additionally manufactured utilizing one or both of at least one dispersant and at least one porogen. 74. The method of any one of claims 66-73, wherein the adsorbent comprises a biocompatible and blood compatible outer coating covalently bonded to the adsorbent by free radical graft polymerization. 74. The method of any one of claims 66-73, wherein the adsorbent is administered prior to administration of supportive care. 74. The method of any one of claims 66-73, wherein the adsorbent is administered concurrently with administration of supportive care. 74. The method of any one of claims 66-73, wherein the adsorbent is administered after administration of supportive care. 82. The method of claim 81, wherein said supportive therapy comprises administration of an immunotherapeutic agent selected from one or more of checkpoint inhibitors, monoclonal antibodies, and bispecific T cell engagers. . 74. The method of any one of claims 66-73, wherein the sorbent comprises residues of one or more of divinylbenzene and ethylvinylbenzene, styrene, and ethylstyrene monomers. 27. The method of any one of claims 1-26, wherein administration for said adsorbent reduces endothelial sequestration of leukocytes and/or increases the presence of leukocytes in areas of infection or injury, and/ or resulting in reduced infection and/or improved healing.

Images